Materiały źródłowe

• #1 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10135776/

  The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. […] The development of HCC is associated with some form of cellular death, which may be either programmed (PCD) (such as apoptosis, necroptosis and autophagy-dependent cell death) or non-programmable (such as pyroptosis and necrosis). Apoptosis is probably the commonest cause of PCD.

• #2 Molecular Pathogenesis of Hepatocellular Carcinoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5075835/

  The pathogenesis of hepatocellular carcinoma (HCC) is a multistep process involving the progressive accumulation of molecular alterations pinpointing different molecular and cellular events. […] There is emerging evidence supporting the importance of cancer metabolism and tumor microenvironment in providing a favorable and supportive niche to expedite HCC development. […] Moreover, recent studies have identified distinct surface markers of cancer stem cell (CSC) in HCC, and they also put forward the profound involvement of altered signaling pathways and epigenetic modifications in CSCs, in addition to the concomitant drug resistance and metastasis. […] Taken together, multiple key genetic and non-genetic factors, as well as liver CSCs, result in the development and progression of HCC.

• #3 Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma

  https://www.mdpi.com/2227-9059/10/12/3202

  Hepatocellular carcinoma (HCC) is the most frequent liver cancer with high lethality and low five-year survival rates leading to a substantial worldwide burden for healthcare systems. HCC initiation and progression are favored by different etiological risk factors including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, non-/and alcoholic fatty liver disease (N/AFLD), and tobacco smoking. […] In molecular pathogenesis, endogenous alteration in genetics (TP53, TERT, CTNNB1, etc.), epigenetics (DNA-methylation, miRNA, lncRNA, etc.), and dysregulation of key signaling pathways (Wnt/β-catenin, JAK/STAT, etc.) strongly contribute to the development of HCC. The multitude and complexity of different pathomechanisms also reflect the difficulties in tailored medical therapy of HCC.

• #4 Hepatocellular carcinoma pathogenesis: from genes to environment | Nature Reviews Cancer

  https://www.nature.com/articles/nrc1934

  Hepatocellular carcinoma (HCC) is one of the most lethal cancers, and affects many of the world’s populations. […] Various aetiologies have been linked to HCC development, the most prominent of which include chronic hepatitis B (HBV) and C (HCV) viral infection, chronic alcohol consumption and aflatoxin-B1-contaminated food. Virtually all cirrhosis-inducing conditions can cause HCC, pointing to important interactions with the host microenvironment. […] HBV-induced hepatocarcinogenesis can involve an array of processes, including host-viral interactions, sustained cycles of necrosis-inflammation-regeneration, viral-endoplasmic-reticulum interactions (induction of oxidative stress), viral integration into the host genome (and associated host DNA deletions) and the targeted activation of oncogenic pathways by various viral proteins.

• #5 Introductory Chapter: Etiology and Pathogenesis of Hepatocellular Carcinoma | IntechOpen

  https://www.intechopen.com/chapters/61816

  Hepatocellular carcinoma (HCC) is the most frequent malignant tumor of the liver with hundreds of thousands of new cases diagnosed each year. […] HCC has several well-known risk factors, which have been proven to strongly associate with the development of HCC. The most common etiological risk factors are hepatotropic viruses: hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis D virus (HDV) and a suggestive evidence is revealed by similar distribution of HCC in areas where these viruses also encounter increasing incidence and it is considered that up to 90% of the diagnosed HCCs develop in context of hidden cirrhosis. […] Cirrhosis is the main underlying cause for most HCC cases, with HBV, and HCV infection often involved in the development of cirrhosis. Approximately 70-90% of liver cancers occur on cirrhosis, and in Western countries, the HCC ratio on cirrhosis exceeds 90%.

• #6 Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma

  https://www.mdpi.com/2227-9059/10/12/3202

  The prognosis of patients with HCC depends highly on performance status and liver function. Therefore, HCC in liver cirrhosis is classified by the updated Barcelona-Clinic-Liver cancer (BCLC) Classification system. […] In this regard, it is evident to identify clinical and molecular subtypes for a better tailored and individualized medicine in systemic therapy of HCC. Due to the global disease burden, it is of utmost importance to better understand HCC pathogenesis to develop new treatments and approaches with promising therapeutic targets. […] The common feature of all these factors is induction of liver cirrhosis as a possible complication. […] Clinical studies have shown that about 8% of all patients with liver cirrhosis develop HCC. […] Approximately 54% of HCC cases are due to HBV infection.

• #7 Introductory Chapter: Etiology and Pathogenesis of Hepatocellular Carcinoma | IntechOpen

  https://www.intechopen.com/chapters/61816

  Hepatocellular carcinoma (HCC) is the most frequent malignant tumor of the liver with hundreds of thousands of new cases diagnosed each year. […] HCC has several well-known risk factors, which have been proven to strongly associate with the development of HCC. The most common etiological risk factors are hepatotropic viruses: hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis D virus (HDV) and a suggestive evidence is revealed by similar distribution of HCC in areas where these viruses also encounter increasing incidence and it is considered that up to 90% of the diagnosed HCCs develop in context of hidden cirrhosis. […] Cirrhosis is the main underlying cause for most HCC cases, with HBV, and HCV infection often involved in the development of cirrhosis. Approximately 70-90% of liver cancers occur on cirrhosis, and in Western countries, the HCC ratio on cirrhosis exceeds 90%.

• #8 Pathology Outlines – Hepatocellular carcinoma overview

  https://www.pathologyoutlines.com/topic/livertumorhcc.html

  Primary malignancy of liver with hepatocellular differentiation […] Most common (> 80%) primary liver malignancy worldwide […] ~80% of hepatocellular carcinoma cases arise in cirrhosis […] Specific subtypes have associated molecular / cytogenetic abnormalities […] Stepwise process (low grade dysplastic nodule → high grade dysplastic nodule → early hepatocellular carcinoma → progressed hepatocellular carcinoma) accompanied by accumulation of molecular alterations […] Molecular alterations include: telomere shortening, TERT activation, cell cycle checkpoint inhibitor inactivation […] TERT promoter mutation is a salient event to hepatocellular carcinoma progression […] ~80% of hepatocellular carcinoma cases in adults arise in cirrhosis […] Chronic viral hepatitis is the leading cause of hepatocellular carcinoma worldwide

• #9 Molecular mechanism of hepatocellular carcinoma

  https://www.oaepublish.com/articles/2394-5079.2018.23

  Hepatocellular carcinoma (HCC) is characterized by a highly heterogenetic pathogenesis with an aggressive clinical course leading to poor survival. […] It is generally accepted that hepatocarcinogenesis is very complex and occurs through a multistep biological process during malignant transformation of normal hepatocytes in which various factors, including genetic and epigenetic alterations, are involved. […] Despite these advances, it remains difficult to effectively treat advanced HCC because most advanced cases are accompanied by poor liver function and liver cirrhosis. […] To this end, further investigation of the molecular pathways involved in hepatocarcinogenesis and tumor progression is indispensable. […] Among the major risk factors for HCC, HBV is the most common causative agent that increases the incidence of HCC in East Asia and sub-Saharan Africa.

• #10 Molecular Pathogenesis of Hepatocellular Carcinoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5075835/

  Molecular alterations at both genetic and epigenetic levels have been shown to drive hepatocarcinogenesis. […] Genome instability is a key driver in human cancers including HCC, and this may result in CNAs with gain or loss in chromosomes of different extents or somatic mutations in the genomes. […] Recently, active NGS-based genome-wide mutational screenings in HCC samples with different etiological backgrounds have been carried out worldwide. […] CTNNB1 and TP53 are the most commonly mutated genes in HCC. […] Apart from the aforementioned putative HCC drivers affecting a wide spectrum of cellular processes, emerging evidence has indicated frequent and recurrent somatic mutations in the promoter area of the TERT (telomerase reverse transcriptase) in various types of cancer. […] One of the distinctive features of HBV DNA is that it can integrate into the human genome, which in turn disrupts the endogenous tumor suppressors and other regulatory genes, or enhances the activity of proto-oncogenes.

• #11 Hepatocellular Carcinoma (HCC): Practice Essentials, Anatomy, Pathophysiology

  https://emedicine.medscape.com/article/197319-overview

  Some of the factors associated with the development of HCC in HBV-infected individuals are as follows: Elevated serum HBV DNA viral load; HBV genotype Risk of HCC appears to be higher with HBV genotypes C and F; HBV mutations Such as in preS, basic core promoter (BCP), or HBx regions; Host factors Such as polymorphisms in KIF1B, HLA-DQ, STAT4, and GRIK1; HBV integration into growth-control genes (eg, TERT), pro-oncogenic genes, or tumor suppressor genes and the oncogenic activity of truncated HBx. […] Genomic sequencing studies for HCC have been performed, and potential driver genes in HCC have been catalogued. Frequently mutated genes identified in large-scale studies, and their functions, include the following: TERT – Maintaining telomere length; TP53 – Tumor suppressor; CTNNB1 – Transcriptional regulator; ARID1A, ARID2 – Chromatin remodeling.

• #12 Genes & Cancer | Pathogenesis to management of hepatocellular carcinoma

  https://www.genesandcancer.com/article/226/text/

  Human HCC has significant clinical, histopathologic, and genomic heterogeneity. […] Multiple genetic events have been associated with the development and pathogenesis of HCC, including mutations, amplifications, deletions, chromosomal rearrangements, and aberrant methylation. […] The most common mutations in HCC are somatic mutations in the promoter of the gene encoding telomerase reverse transcriptase (TERT), which are present in 5460% of all HCC cases. […] Telomere shortening is accentuated in chronic liver injury, resulting in apoptosis and the inability of the liver to regenerate fully, and is likely linked to the pathogenesis of HCC. […] HCC is also associated with a high frequency of mutations in several other genes. […] Gene amplification and deletions, as well as chromosomal rearrangements, are structural alterations that play an important role in the carcinogenesis of HCC.

• #13 Hepatocellular Carcinoma (HCC): Practice Essentials, Anatomy, Pathophysiology

  https://emedicine.medscape.com/article/197319-overview

  Some of the factors associated with the development of HCC in HBV-infected individuals are as follows: Elevated serum HBV DNA viral load; HBV genotype Risk of HCC appears to be higher with HBV genotypes C and F; HBV mutations Such as in preS, basic core promoter (BCP), or HBx regions; Host factors Such as polymorphisms in KIF1B, HLA-DQ, STAT4, and GRIK1; HBV integration into growth-control genes (eg, TERT), pro-oncogenic genes, or tumor suppressor genes and the oncogenic activity of truncated HBx. […] Genomic sequencing studies for HCC have been performed, and potential driver genes in HCC have been catalogued. Frequently mutated genes identified in large-scale studies, and their functions, include the following: TERT – Maintaining telomere length; TP53 – Tumor suppressor; CTNNB1 – Transcriptional regulator; ARID1A, ARID2 – Chromatin remodeling.

• #14 KEGG DISEASE: Hepatocellular carcinoma

  https://www.genome.jp/entry/H00048

  Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and one of the rare human neoplasms etiologically linked to viral factors. […] It has been shown that, after HBV/HCV infection and alcohol or aflatoxin B1 exposure, genetic and epigenetic changes occur. […] The recurrent mutated genes were found to be highly enriched in multiple key driver signaling processes, including telomere maintenance, TP53, cell cycle regulation, the Wnt/beta-catenin pathway (CTNNB1 and AXIN1), the phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. […] Recent studies using whole-exome sequencing have revealed recurrent mutations in new driver genes involved in the chromatin remodelling (ARID1A and ARID2) and the oxidative stress (NFE2L2) pathways. […] Molecular pathogenesis of human hepatocellular carcinoma. […] Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.

• #15 Hepatocellular carcinoma: Epidemiology, pathogenesis and surveillance – implications for sub-Saharan Africa

  http://www.scielo.org.za/scielo.php?script=sci_arttext&pid=S0256-95742018000900011

  The aetiology of HCC influences the genetic aberrations found in HCCs. HBV is a DNA virus that can induce HCC through several potential mechanisms: viral genome integration into the host genome; immune-mediated destruction and concomitant regeneration of HBV-infected hepatocytes; and the activity of HBV X (HBx) protein, a key regulatory protein in HBV replication that acts as a cofactor in the development of HCC. In contrast, HCV appears to induce HCC by more indirect methods, mediating inflammation and inducing recurrent cycles of cell injury, repair and regeneration that result in premature senescence and activation of a fibrogenic repair response in the liver. […] The most significant mutations associated with hepatocellular carcinoma include mutations in the telomerase reverse transcriptase (TERT) promoter (30 – 60%), tumor protein p53 (TP53) (18 – 50%), and -catenin (CTNNB1) (18 – 40%).

• #16 Hepatocellular carcinoma pathogenesis: from genes to environment | Nature Reviews Cancer

  https://www.nature.com/articles/nrc1934

  Genomic instability is a common feature of human HCC. Various mechanisms are thought to contribute, including telomere erosion, chromosome segregation defects and alterations in the DNA-damage-response pathways. […] There are many genomic alterations in HCC. Comparative genomic hybridization studies so far have pointed to frequent chromosomal gains in 1q, 6p, 8q, 11q and 17q, and losses in 1p, 4q, 8p, 13q and 17p. Attempts have also been made to relate particular genomic alterations to aetiology and tumour-stage, albeit to a limited extent. […] Gene-expression analyses of human HCCs have led to the successful molecular classification of HCCs on the basis of prognosis, aetiology and intrahepatic recurrence. […] Many challenges and opportunities exist in this field, including the need for a more detailed and clinically grounded genomic characterization of human HCCs, deeper understanding of the mechanisms of genomic instability, host-viral interactions, microenvironmental processes (inflammation and cirrhosis), cell of origin in hepatocarcinogenesis and the identification of biomarkers to identify early stage disease as well as those at greatest risk of developing HCC.

• #17 Molecular Pathogenesis of Hepatocellular Carcinoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5075835/

  Molecular alterations at both genetic and epigenetic levels have been shown to drive hepatocarcinogenesis. […] Genome instability is a key driver in human cancers including HCC, and this may result in CNAs with gain or loss in chromosomes of different extents or somatic mutations in the genomes. […] Recently, active NGS-based genome-wide mutational screenings in HCC samples with different etiological backgrounds have been carried out worldwide. […] CTNNB1 and TP53 are the most commonly mutated genes in HCC. […] Apart from the aforementioned putative HCC drivers affecting a wide spectrum of cellular processes, emerging evidence has indicated frequent and recurrent somatic mutations in the promoter area of the TERT (telomerase reverse transcriptase) in various types of cancer. […] One of the distinctive features of HBV DNA is that it can integrate into the human genome, which in turn disrupts the endogenous tumor suppressors and other regulatory genes, or enhances the activity of proto-oncogenes.

• #18 Molecular Pathogenesis of Hepatocellular Carcinoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5075835/

  Epigenetic alterations are reversible modifications at the genome level without involving changes of the DNA sequence. […] The valuable information generated by various genomic, transcriptomic and epigenetic alterations provide us with a comprehensive assessment about how these changes may affect key signaling pathways supporting the development of HCC. […] With efforts from studies pinpointing the multiple aspects of HCC pathogenesis, knowledge has been accumulating on the stochastic molecular alterations targeting different cancer hallmark events. […] The intimate relationship between tumor microenvironment and cancer metabolism has been explored in a number of studies and new data are rapidly emerging. […] In HCC, hypoxia-inducible factor (HIF)-1-induced glycolysis is associated with biological aggressiveness.

• #19 Genes & Cancer | Pathogenesis to management of hepatocellular carcinoma

  https://www.genesandcancer.com/article/226/text/

  Epigenetic alterations include changes in methylation, chromatin remodeling, and micro-RNAs. […] Animal models allow for the integration of the genomic and molecular characterization of human HCC samples in a way that permits for the discovery and testing of biomarkers and novel HCC therapies. […] The NASH-HCC model is MUP-uPA mice fed a high-fat diet (HFD), resulting in steatohepatitis resembling human NASH. […] The immune component of the HCC microenvironment has been of great interest with the recent approval of immunotherapies, such as immune checkpoint inhibitors, for advanced stage HCC. […] The aberrant activity of the TGF- pathway is involved in nearly 40% of HCCs, and deficiency of this pathway is observed in the cancer stem cell signature of HCC. […] While personalized medicine has become a practical reality in other cancers, HCC has been difficult to target with specific treatments based on molecular profiling. […] One of the main reasons for targeted therapies failure is tumor heterogeneity (inter and intra-subject). […] A challenge to developing therapies is that somatic mutations occur in genes whose products are not easily or safely druggable, such as mutated forms of TERT, TP53, CTNNB1, and MYC.

• #20 Etiology, Mechanism and Treatment of Liver Cancer | IntechOpen

  https://www.intechopen.com/chapters/84187

  The development of liver cancer is a multistage and branched process of morphological and genetic traits. The tumor in liver is not only associated with cellular malignancy but also linked with genome abnormality, which ultimately cause neoplastic growth. […] The hepatic-carcinogenesis emerged by two most important oncogenic events such as telomerase reverse transcriptase (TERT) activation and MYC activation. […] The epigenetic alterations include DNA hypo-methylation or hyper-methylation, chromatin remodeling, dysregulation of histone adaptation patterns, aberrant expression of micro-RNAs (miRNAs) and long noncoding RNAs (lncRNAs) are allied with HCC. […] The signaling pathways upregulate or downregulate according to etiological factors of HCC. […] The cancer stem cell (CSC) also involved in progression, aggressiveness and metastasis of HCC, by the action of several surface markers such as epithelial cell adhesion molecule (EpCAM), CD13, CD44, CD90 and CD133.

• #21 Long noncoding RNAs in hepatocellular carcinoma: Novel insights into their mechanism

  https://wjgnet.com/1948-5182/full/v7/i28/2781.htm

  Recent studies have also elucidated that lncRNAs possess a significant role in epigenetic regulation. […] Via regulating gene expression by miscellaneous mechanisms, including genomic imprinting, chromatin modification, regulation of protein function, transcription and post-transcriptional processing, lncRNAs are involved in multitudinous physiological functions and pathological processes. […] Given the fact that such large scales of lncRNAs are aberrantly regulated in HCC, it is of highly possibility that lncRNAs are directly associated with carcinogenesis of HCC. […] In this review, we concentrated on cancer-related lncRNAs which have been validated in human HCC. Furthermore, we summarized their mechanism and signaling pathways in HCC. […] Abnormal expressed lncRNAs have been found to be associated with hepatocarcinogenesis and play a key role in metastasis and prognosis.

• #22 The Mechanism of Hepatitis B Virus X Gene in Promoting Hepatocellular Carcinoma

  https://www.fortunejournals.com/articles/the-mechanism-of-hepatitis-b-virus-x-gene-in-promoting-hepatocellular-carcinoma.html

  HBx protein cannot directly bind to the DNA, but can trans-regulate gene transcription via interacting with various protein factors to activate promoters and enhancers, thus affecting the occurrence and development of HCC. […] HBx can stimulate HAT1 promoter by co-activating Sp1 to induce HAT1 expression, contributing to the assembly and epigenetic regulation of HBV cccDNA minichromosomes. […] HBx gene and its encoded protein are widely involved in the process of chronic hepatitis, cirrhosis, and liver cancer by promoting HBV replication, integration into the host genome, and evolution. The inflammation microenvironment interacting with APOBECs can both promote HBV and host cells evolution, which leads to poor prognosis of HCC patients. […] Epidemiological evidence indicates that HBx mutants are closely related to HBV-HCC and gradually accumulate during the development of HCC. Mutant HBx has a stronger carcinogenic ability than wild-type HBx and is associated with antiviral treatment resistance. In recent years, HBx has been found to play an important role in the occurrence, recurrence, metastasis and immune escape of HCC via numerous new mechanisms, such as trans-activation and trans-repression, epigenetic modification, activation of oncogenic pathways, metabolic disorders and drug resistance.

• #23 KEGG DISEASE: Hepatocellular carcinoma

  https://www.genome.jp/entry/H00048

  Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and one of the rare human neoplasms etiologically linked to viral factors. […] It has been shown that, after HBV/HCV infection and alcohol or aflatoxin B1 exposure, genetic and epigenetic changes occur. […] The recurrent mutated genes were found to be highly enriched in multiple key driver signaling processes, including telomere maintenance, TP53, cell cycle regulation, the Wnt/beta-catenin pathway (CTNNB1 and AXIN1), the phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. […] Recent studies using whole-exome sequencing have revealed recurrent mutations in new driver genes involved in the chromatin remodelling (ARID1A and ARID2) and the oxidative stress (NFE2L2) pathways. […] Molecular pathogenesis of human hepatocellular carcinoma. […] Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.

• #24 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10135776/

  The abnormal activation of the oncogenic phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling is associated with HCC. […] The deregulation of Wnt/-catenin signaling is critical in human HCC. […] The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. […] Autophagy is implicated in the initiation and progression of HCC in many ways. It is closely associated with inflammation, which is a critical factor in HCC development. […] The activation of the Wnt/-catenin pathway favors the development of HCC, as previously mentioned. […] The activation of autophagy may lead to the induction of apoptosis and the inhibition of the growth of hepatoma cells.

• #25 Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma

  https://www.mdpi.com/2227-9059/10/12/3202

  Another 31% of HCC are due to HCV infection. […] In addition to viral factors, toxins also play a crucial role in the development of HCC. […] Inflammatory processes, hepatocyte necrosis and regenerative processes associated with oxidative stress condition the development of hepatic cirrhosis with regular alcohol consumption. […] Metabolic diseases favor liver steatosis as a precursor to fibrosis or cirrhosis. […] Somatic mutations are the most common cause for a healthy cell turning into an abnormal cell. […] Molecular studies have identified the most frequent alterations in HCC, including mutations in the TERT promoter, TP53, CTNNB1, and epigenetic aberrations. […] The Wnt/β-catenin pathway is one of the best-studied signaling cascades. […] The most prevalent mutations are in CTNNB1, which destabilizes and translocates β-catenin into the nucleus.

• #26 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://www.mdpi.com/2227-9059/11/4/1166

  The deregulation of Wnt/β-catenin signaling is critical in human HCC. […] The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. […] Autophagy is implicated in the initiation and progression of HCC in many ways. […] The activation of the Wnt/β-catenin pathway favors the development of HCC. […] The mechanisms of HCC induction and progression in HCV infection have been recently reviewed in detail. […] The role of ferroptosis in HCC initiation and progression has been extensively reviewed. […] The manipulation of either autophagy or apoptosis will improve the treatment outcomes of a difficult-to-treat tumor.

• #27 Molecular mechanism of hepatocellular carcinoma

  https://www.oaepublish.com/articles/2394-5079.2018.23

  Chronic HBV infection enables viral DNA to integrate into the host genome, leading to an oncogenic transformation. […] These findings suggest a significant association between HBV integration and hepatocarcinogenesis. […] Accumulating evidence has shown that HBx plays important roles in hepatocarcinogenesis. […] Several mechanisms by which HBx may function at the molecular and cellular levels are as follows: (1) transactivation of promoters of cAMP response element binding protein (CREB) response element (CRE)-containing genes, including the oncogene Yes-associated protein (YAP); (2) alteration of the DNA specificity of CREB and activating transcription factor 2 (ATF-2), resulting in binding and activation of the HBV enhancer; (3) modulation of the DNA binding specificity of the p53 tumor suppressor, resulting in altered expression of its target genes; and (4) regulation of cellular signaling pathways, such as activation of the Ras-Raf-MAPK pathway, Src-dependent pathway, PI3K-Akt pathway, inflammation-associated NF-kB/STAT-3 pathways, and wnt/-catenin pathway.

• #28 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10135776/

  The abnormal activation of the oncogenic phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling is associated with HCC. […] The deregulation of Wnt/-catenin signaling is critical in human HCC. […] The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. […] Autophagy is implicated in the initiation and progression of HCC in many ways. It is closely associated with inflammation, which is a critical factor in HCC development. […] The activation of the Wnt/-catenin pathway favors the development of HCC, as previously mentioned. […] The activation of autophagy may lead to the induction of apoptosis and the inhibition of the growth of hepatoma cells.

• #29 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://www.mdpi.com/2227-9059/11/4/1166

  Autophagy is an important degradation process of cellular contents, leading to the recirculation of structural components of the cell and improved survival. […] The purpose of this review is to present the current views on HCC pathogenesis and the complex interplay of autophagy, apoptosis and ferroptosis in the pathophysiology and treatment of HCC. […] Inflammation is an important pathogenetic factor irrespective of the etiology of the liver disease that leads to HCC. […] Chronic ER stress and increased UPR activity have been implicated in the development of HCC and are present in HCC tumors irrespective of grade or stage. […] The abnormal activation of the oncogenic phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling is associated with HCC.

• #30 Long noncoding RNAs in hepatocellular carcinoma: Novel insights into their mechanism

  https://wjgnet.com/1948-5182/full/v7/i28/2781.htm

  Hepatocellular carcinoma (HCC), one of the most common histologic subtype of primary liver cancers, accounting for 70%-85% of liver cancer cases in most countries, is the third-leading cause of worldwide mortality for various cancers. […] In addition, many key signal transduction pathways have been verified to be involved in the pathogenesis of HCC, including PI3K/Akt/mTOR pathway, Raf/MAPK/ERK pathway, Jak/Stat pathway, WNT-b-catenin pathway, so on and so forth. […] Recently, human genome analysis in non-protein coding has made new progress. It discovers massive transcription of large RNA transcripts which lack coding protein function, termed as long noncoding RNAs (lncRNAs). […] NcRNAs were once thought to be body garbage or transcriptional noise. However, accumulating reports have demonstrated that miRNAs and lncRNAs play valid regulatory roles in cancer.

• #31 Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma

  https://www.mdpi.com/2227-9059/10/12/3202

  The JAK/STAT signaling pathway has a pivotal role in various cellular functions and can be activated by different cytokines and growth factors, such as interleukins, interferons, and EGFs. […] The transforming growth factor-β (TGF-β) signaling pathway regulates various physiological aspects in embryogenesis and adult tissue homeostasis.

• #32 Investigating the mechanism of hepatocellular carcinoma progression by constructing genetic and epigenetic networks using NGS data identification and big… | Oncotarget

  https://www.oncotarget.com/article/13100/text/

  The differentially expressed miRNAs, mir-93, mir-101, mir-182, mir-340, mir-590 and let-7e, and the differentially methylated genes, BMPR1B, CDC25B, DAXX, DDIT3, FOS, JUN, MAP2K4, MAP4K2, MYC, NFKB1, NFKB2, PDGFB, PPP3CA, RAP1A, TAB2, TNFRSF1A and TRAF2, regulate cell proliferation, apoptotic process, cell cycle, cell survival and metastasis through TGF-beta and MAPK pathways in the switch between stage II HCC and stage III HCC. […] The differentially expressed miRNAs, mir-182, mir-340, mir-374a, mir-590 and let-7a, and the differentially methylated genes, AKT1, BMPR1B, CNTFR, DAXX, GDF6, GNA12, HRAS, IL1B, IL1R1, IL7R, JUN, MAP3K2, MYC, NFKB1, NFKB2, PDGFB, RAP1A, STAT3 and TRAF2, regulate cell proliferation, apoptotic process, cell cycle, cell survival and metastasis through TGF-beta, MAPK and JAK-STAT pathways in the switch between stage III HCC and stage IV HCC.

• #33 Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma

  https://www.mdpi.com/2227-9059/10/12/3202

  The JAK/STAT signaling pathway has a pivotal role in various cellular functions and can be activated by different cytokines and growth factors, such as interleukins, interferons, and EGFs. […] The transforming growth factor-β (TGF-β) signaling pathway regulates various physiological aspects in embryogenesis and adult tissue homeostasis.

• #34 Genes & Cancer | Pathogenesis to management of hepatocellular carcinoma

  https://www.genesandcancer.com/article/226/text/

  Epigenetic alterations include changes in methylation, chromatin remodeling, and micro-RNAs. […] Animal models allow for the integration of the genomic and molecular characterization of human HCC samples in a way that permits for the discovery and testing of biomarkers and novel HCC therapies. […] The NASH-HCC model is MUP-uPA mice fed a high-fat diet (HFD), resulting in steatohepatitis resembling human NASH. […] The immune component of the HCC microenvironment has been of great interest with the recent approval of immunotherapies, such as immune checkpoint inhibitors, for advanced stage HCC. […] The aberrant activity of the TGF- pathway is involved in nearly 40% of HCCs, and deficiency of this pathway is observed in the cancer stem cell signature of HCC. […] While personalized medicine has become a practical reality in other cancers, HCC has been difficult to target with specific treatments based on molecular profiling. […] One of the main reasons for targeted therapies failure is tumor heterogeneity (inter and intra-subject). […] A challenge to developing therapies is that somatic mutations occur in genes whose products are not easily or safely druggable, such as mutated forms of TERT, TP53, CTNNB1, and MYC.

• #35 Investigating the mechanism of hepatocellular carcinoma progression by constructing genetic and epigenetic networks using NGS data identification and big… | Oncotarget

  https://www.oncotarget.com/article/13100/text/

  The differentially expressed miRNAs, mir-93, mir-101, mir-182, mir-340, mir-590 and let-7e, and the differentially methylated genes, BMPR1B, CDC25B, DAXX, DDIT3, FOS, JUN, MAP2K4, MAP4K2, MYC, NFKB1, NFKB2, PDGFB, PPP3CA, RAP1A, TAB2, TNFRSF1A and TRAF2, regulate cell proliferation, apoptotic process, cell cycle, cell survival and metastasis through TGF-beta and MAPK pathways in the switch between stage II HCC and stage III HCC. […] The differentially expressed miRNAs, mir-182, mir-340, mir-374a, mir-590 and let-7a, and the differentially methylated genes, AKT1, BMPR1B, CNTFR, DAXX, GDF6, GNA12, HRAS, IL1B, IL1R1, IL7R, JUN, MAP3K2, MYC, NFKB1, NFKB2, PDGFB, RAP1A, STAT3 and TRAF2, regulate cell proliferation, apoptotic process, cell cycle, cell survival and metastasis through TGF-beta, MAPK and JAK-STAT pathways in the switch between stage III HCC and stage IV HCC.

• #36 Hepatocellular carcinoma pathogenesis: from genes to environment | Nature Reviews Cancer

  https://www.nature.com/articles/nrc1934

  Hepatocellular carcinoma (HCC) is one of the most lethal cancers, and affects many of the world’s populations. […] Various aetiologies have been linked to HCC development, the most prominent of which include chronic hepatitis B (HBV) and C (HCV) viral infection, chronic alcohol consumption and aflatoxin-B1-contaminated food. Virtually all cirrhosis-inducing conditions can cause HCC, pointing to important interactions with the host microenvironment. […] HBV-induced hepatocarcinogenesis can involve an array of processes, including host-viral interactions, sustained cycles of necrosis-inflammation-regeneration, viral-endoplasmic-reticulum interactions (induction of oxidative stress), viral integration into the host genome (and associated host DNA deletions) and the targeted activation of oncogenic pathways by various viral proteins.

• #37 Introductory Chapter: Etiology and Pathogenesis of Hepatocellular Carcinoma | IntechOpen

  https://www.intechopen.com/chapters/61816

  HBV is regarded as the main etiological factor that generates multiple pathological changes inside the liver structure, being responsible for the development of HCC over time. […] Hepatocarcinogenesis generated by chronic HBV infection is a multistep process that implies rearrangement of the intracellular DNA leading to inflammation of the hepatocytes, accompanied by an increased rate of proliferation. […] Recent studies enhance the importance of HBV X protein, suggesting that pathways like p38MAPK and PI-3 K/AKT are used in order to increase the invasive potential of HBV infection. […] Chronic hepatitis C infection is a major risk factor for developing HCC. […] Almost all HCV-related hepatocarcinomas occur due to cirrhosis or chronic inflammation. […] The risk of developing HCC for patients with underlying autoimmune hepatitis still remains unclear.

• #38 The Mechanism of Hepatitis B Virus X Gene in Promoting Hepatocellular Carcinoma

  https://www.fortunejournals.com/articles/the-mechanism-of-hepatitis-b-virus-x-gene-in-promoting-hepatocellular-carcinoma.html

  HBV replication, integration, and evolution are the main factors in the occurrence and development of HBV-HCC. HBx (HBV X) is a 17 kDa protein expressed from the X open reading frame (ORF) of HBV, with little sequence homology to any known genes, hence the name “X”. HBx is a multifunctional factor that can regulate the HBV replication and activate cancer-promoting signal pathways. […] During HBV-induced hepatocarcinogenesis, HBV typically adapts to the inflammatory microenvironment by integrating into the human genome and accumulating mutations. HBx C-terminal truncation (Ct-HBx) resulting from HBV integration has been suggested to impact the development of HCC. HBx mutants, generated and accumulated in the chronic inflammation caused by HBV, play a complicated role in HCC. Therefore, understanding the mechanism of HBx and its mutants in HCC can help understand the pathogenesis of HBV-HCC and provide novel prophylactic and therapeutic options for HBV-HCC.

• #39 The Mechanism of Hepatitis B Virus X Gene in Promoting Hepatocellular Carcinoma

  https://www.fortunejournals.com/articles/the-mechanism-of-hepatitis-b-virus-x-gene-in-promoting-hepatocellular-carcinoma.html

  HBV can integrate into the human genome, thus contributing to genomic instability and hepatocarcinogenesis. Approximately 40% of HBV breakpoints in the HBV genome are located within a 1,800-bp region where the viral enhancer, X gene, and core gene are located. HBx integrates into the cancer-related genes such as TERT, MLL4, and CCNE1 and affects their expression. […] HBV integration can produce HBV-human chimeric transcripts that exert oncogenic effects. HBV-human chimeric transcripts are mainly fusions of HBx gene with repetitive elements within introns of human genes such as long interspersed nuclear elements (LINEs). HBx-LINE1 chimeric transcript, as a long non-coding RNA, down-regulates the expression of miR-122, leading to increased activity of Wnt/ β-catenin pathway, inducing colony formation, invasion, and migration, and leading to the occurrence and development of tumors.

• #40 Molecular Mechanism of HBx Protein Function in HBv Related Hepatocellular Carcinoma Carcinogenesis – MedCrave online

  https://medcraveonline.com/GHOA/molecular-mechanism-of-hbx-protein-function-in-hbv-related-hepatocellular-carcinoma-carcinogenesis.html

  Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer mortality. Based on significant differences in the geographic distribution of HCC incidence, chronic hepatitis B virus (HBV) infection has been identified as a major risk factor for HCC. The mechanisms underlying HBV-induced malignant transformation remain ambiguous; however, previous research has suggested that HBV X (HBx) protein has a crucial function in the pathogenesis of HCC. […] This minireview will focus on studies on the molecular mechanisms of HBx in HCC pathogenesis. […] Previous research on the pathogenesis of HBx-induced HCC and on other aetiological forms of the tumour had suggested the role of several factors in HCC pathogenesis, including DNA repair, HBx methylation, noncoding RNA and HBx mutation. Current studies indicate that DNA repair is one of the driving mechanisms of carcinogenesis. […] Na et al. suggested that the physical interaction of HBx and poly ADP-ribose polymerase 1 (PARP1) accelerates DNA damage by inhibiting recruitment of the DNA repair complex to the damaged DNA sites, which may lead to the onset of hepatocarcinogenesis. […] Epigenetic changes suggest that HBx can upregulate DNA methyltransferase 1 (DNMT1) and DNMT3A through transactivation. Therefore, HBx affects DNMTs to inactivate tumour suppressor genes or cause chromosomal instability, thus serving an increasingly important function in hepatocarcinogenesis. […] With the development of new techniques, the interaction between HBx and ncRNAs, including micro RNAs and long ncRNAs (lncRNA), is becoming evident in the development of HCC. […] HBx-upregulated lncRNA UCA1 promotes cell growth and tumourigenesis by recruiting EZH2 and repressing p27Kip1/CDK2 signalling. […] In short, HBx mutations promote tumour malignancy. However, the detailed mechanism needs further investigation.

• #41 Pathology Outlines – Hepatocellular carcinoma overview

  https://www.pathologyoutlines.com/topic/livertumorhcc.html

  Hepatitis B virus: Direct oncogenic effect by integration of the HBV DNA into the host genome, which subsequently induces genomic instability and mutagenesis of cancer related genes, including p53 and WNT / β catenin pathway; can cause hepatocellular carcinoma without antecedent cirrhosis […] Core HCV proteins (NS5A and NS3) induce oxidative stress, which eventually results in activation of NFκB and MAPK pathway, leading to cell proliferation and alteration of apoptotic pathway […] Nonalcoholic fatty liver disease (NAFLD): Increased prevalence due to metabolic syndrome, obesity and type 2 diabetes; insulin resistance leads to increased insulin-like growth factor 1 (IGF1), which eventually activates PI3K and MAPK pathways, leading to cell proliferation and inhibition of apoptosis […] Aflatoxin B1 reacts with DNA to form mutagenic adducts, leading to codon 249 mutation of TP53 […] ~5% of hepatocellular adenomas undergo malignant transformation […] Stepwise process (low grade dysplastic nodule → high grade dysplastic nodule → early hepatocellular carcinoma → progressed hepatocellular carcinoma) accompanied by accumulation of molecular alterations

• #42 Hepatocellular carcinoma pathogenesis: from genes to environment | Nature Reviews Cancer

  https://www.nature.com/articles/nrc1934

  HCV-induced hepatocarcinogenesis also provokes similar biological processes, but is associated with a propensity of HCV to evade the host’s immune responses and to promote cirrhosis. […] Alcohol-induced hepatocarcinogenesis is associated with the induction of inflammation and, consequently, cycles of hepatocyte necrosis and regeneration, oxidative stress and cirrhosis. Aflatoxin-B1-induced hepatocarcinogenesis is mostly associated with carcinogenic mutations. […] Various genetic events have been associated with the development of HCC, such as the inactivation of the tumour suppressor p53, mutations in -catenin, overexpression of various ErbB receptor family members and overexpression of the Met receptor. In addition, various cancer-relevant genes seem to be targeted on the epigenetic level (methylation) in human HCC.

• #43 Pathogenesis of hepatitis C virus-related hepatocellular carcinoma: evidence from recent studies – Maruyama – Journal of Public Health and Emergency

  https://jphe.amegroups.org/article/view/7483/html

  Hepatocellular carcinoma (HCC) represents primary liver cancer and is problematic worldwide because it is the major reason for cancer-related death. […] There are possible mechanisms of HCV-related HCC development, which include, immune response, inflammation, fibrosis, lipid metabolism and steatosis, neoangiogenesis, and genetic and epigenetic factors, being associated with high cancer incidence. […] Chronic inflammation by HCV infection may provide an indirect effect on hepatocarcinogenesis, as well as an increase of reactive oxygen species (ROS), which leads to hepatocellular damage or death. […] Chronic inflammation due to HCV infection accounts for the development of liver fibrosis, which is a risk factor for the occurrence of HCC. […] The HCV infection is closely related to the development of liver steatosis/steatohepatitis.

• #44 Molecular mechanism of hepatocellular carcinoma

  https://www.oaepublish.com/articles/2394-5079.2018.23

  HCV is a major risk factor of HCC, and that chronic HCV infection induces liver fibrosis and cirrhosis, ultimately resulting in HCC. […] Several studies have provided evidence for a direct role of HCV in the pathogenesis of HCC. […] Alcohol consumption, particularly over-consumption, is a serious global health problem. […] In general, heavy alcohol consumption leads to fatty liver, alcoholic steatohepatitis (ASH), cirrhosis, and eventually, HCC. […] The process of liver injury occurs through activation of oxidative stress, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, autophagy and intrahepatic NKT and CD8+ T cells. […] The hepatic microenvironment of NASH, which is considered to be a proinflammatory milieu, plays an important role in the development and progression of HCC.

• #45 Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infect | JHC

  https://www.dovepress.com/hepatocellular-carcinoma-mechanisms-associated-with-chronic-hcv-infect-peer-reviewed-fulltext-article-JHC

  Hepatitis C virus (HCV) infection is the major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). The mechanisms of HCC initiation, growth, and metastasis appear to be highly complex due to the decade-long interactions between the virus, immune system, and overlapping bystander effects of host metabolic liver disease. […] The host-related mechanisms that drive the risk of HCC in the absence of the virus are unknown. This review describes the multifaceted mechanisms that create a tumorigenic environment during chronic HCV infection. […] The evolution of HCC from cirrhosis is a pathological adaptive response to ISR. Only 13% of patients with chronic HCV infection develop HCC after 30 years and HCV does not infect HCC tumor cells as compared to surrounding non-tumorous hepatocytes, supporting the conclusion that HCV is not directly oncogenic. It is possible that HCV infection creates a tumorigenic environment that promote cellular transformation of uninfected hepatocytes through a bystander mechanism as seen in the case of colorectal cancer associated with Fusobacterium nucleatum and gastric cancer related to Helicobacter pylori.

• #46 Pathogenesis of hepatitis C virus-related hepatocellular carcinoma: evidence from recent studies – Maruyama – Journal of Public Health and Emergency

  https://jphe.amegroups.org/article/view/7483/html

  Hypervascularity is a typical hemodynamic appearance of HCC, supported by studies showing increased microvascular density in patients with HCV-related liver diseases. […] Investigators have shown the influence of gene mutations on hepatocarcinogenesis. […] There is a close linkage between the altered regulation of epigenetic mechanisms and the development of HCC. […] HCV-induced HCC is a well-defined target for cancer prevention. However, the mechanism of HCC development due to HCV infection is complicated with multiple possible pathways, accompanied by the interactions between host and viral responses.

• #47 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10135776/

  The cells of origin of HCC are not clear. Experimental evidence supports the implication of transformed mature hepatocytes as the cell of origin, but also the possibility that the source is liver stem cells. […] HCC is the result of either mutations, such as those in the TERT promoter or p53 suppressor gene, or epigenetic modifications. Some of them are directly involved or activate important signaling pathways leading to HCC. […] In general, three mechanisms are implicated in the initiation and progress of HCC, namely, persistent liver inflammation, endoplasmic reticulum (ER) stress and abnormalities of cell signaling pathways. Inflammation is an important pathogenetic factor irrespective of the etiology of the liver disease that leads to HCC. […] Chronic ER stress and increased UPR activity have been implicated in the development of HCC and are present in HCC tumors irrespective of grade or stage.

• #48 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://www.mdpi.com/2227-9059/11/4/1166

  Autophagy is an important degradation process of cellular contents, leading to the recirculation of structural components of the cell and improved survival. […] The purpose of this review is to present the current views on HCC pathogenesis and the complex interplay of autophagy, apoptosis and ferroptosis in the pathophysiology and treatment of HCC. […] Inflammation is an important pathogenetic factor irrespective of the etiology of the liver disease that leads to HCC. […] Chronic ER stress and increased UPR activity have been implicated in the development of HCC and are present in HCC tumors irrespective of grade or stage. […] The abnormal activation of the oncogenic phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling is associated with HCC.

• #49 Molecular mechanism of hepatocellular carcinoma

  https://www.oaepublish.com/articles/2394-5079.2018.23

  HCV is a major risk factor of HCC, and that chronic HCV infection induces liver fibrosis and cirrhosis, ultimately resulting in HCC. […] Several studies have provided evidence for a direct role of HCV in the pathogenesis of HCC. […] Alcohol consumption, particularly over-consumption, is a serious global health problem. […] In general, heavy alcohol consumption leads to fatty liver, alcoholic steatohepatitis (ASH), cirrhosis, and eventually, HCC. […] The process of liver injury occurs through activation of oxidative stress, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, autophagy and intrahepatic NKT and CD8+ T cells. […] The hepatic microenvironment of NASH, which is considered to be a proinflammatory milieu, plays an important role in the development and progression of HCC.

• #50 Pathophysiology of liver cirrhosis and risk correlation between immune status and the pathogenesis of hepatocellular carcinoma

  https://www.oaepublish.com/articles/2394-5079.2024.141

  The role of immune dysfunction in HCC risk stratification and screening remains underexplored, particularly in elderly and immunocompromised populations. […] The etiology and the duration of the cirrhotic process significantly influence the risk of HCC. […] Chronic liver injury, regardless of its etiology, establishes a proinflammatory microenvironment that modifies immune and stromal cell interactions within the liver. […] The inflammatory microenvironment in CLD exacerbates hepatocellular stress through various mechanisms, including mitochondrial dysfunction, epigenetic modifications, DNA damage, and chromosomal alterations. […] HCC development is driven by a combination of genetic and epigenetic alterations, chronic inflammation, and immune dysfunction. […] These molecular events synergize with immune dysfunction, promoting the escape of precancerous hepatocytes from immune surveillance and propelling the progression toward HCC.

• #51 The Mechanism of Hepatitis B Virus X Gene in Promoting Hepatocellular Carcinoma

  https://www.fortunejournals.com/articles/the-mechanism-of-hepatitis-b-virus-x-gene-in-promoting-hepatocellular-carcinoma.html

  Random HBV genome integration can lead to truncation of the HBV genome, especially at the C-terminal of the HBx gene. The generation of C-terminal truncated HBx (Ct-HBx) is a common event in the occurrence and development of HCC. Many different Ct-HBx have been found in the HBV infector, cirrhosis, and HCC patient, and usually demonstrate a stronger pro-carcinogenic effects compared to the full-length of HBx. Ct-HBx can synergistically down-regulate the expression of TXNIP with NFATC2, leading to glucose metabolism reprogramming, thus initiating the occurrence of HCC and promoting the migration and invasion of cancer cells. […] Chronic inflammation is a prerequisite for the development of cancers. The chronic non-resolving inflammation status of the liver is mainly caused by HBV infection. Under this status, both HBV and host cells undergo an evolutionary process of “mutation–selection–adaptation”, which promotes the occurrence and progression of HCC. […] The family of cytidine deaminases and their analogues called “apolipoprotein B mRNA editing enzyme catalytic polypeptides (APOBECs),” play critical roles in various biologic processes, and are trans-activated by pro-inflammatory molecules. APOBECs can impact HBV replication and induce HBV hypermutation via cytidine deamination. The expression level of APOBEC3s was significantly correlated with HBV quasispecies complexity. Among the HBV genome, APOBEC3s prefer to cause the mutations in HBx. APOBEC3-mediated HBx mutants cause a gain of function that enhances the colony-forming ability and proliferative capacity of neoplastic cells.

• #52 Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infect | JHC

  https://www.dovepress.com/hepatocellular-carcinoma-mechanisms-associated-with-chronic-hcv-infect-peer-reviewed-fulltext-article-JHC

  Hepatitis C virus (HCV) infection is the major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). The mechanisms of HCC initiation, growth, and metastasis appear to be highly complex due to the decade-long interactions between the virus, immune system, and overlapping bystander effects of host metabolic liver disease. […] The host-related mechanisms that drive the risk of HCC in the absence of the virus are unknown. This review describes the multifaceted mechanisms that create a tumorigenic environment during chronic HCV infection. […] The evolution of HCC from cirrhosis is a pathological adaptive response to ISR. Only 13% of patients with chronic HCV infection develop HCC after 30 years and HCV does not infect HCC tumor cells as compared to surrounding non-tumorous hepatocytes, supporting the conclusion that HCV is not directly oncogenic. It is possible that HCV infection creates a tumorigenic environment that promote cellular transformation of uninfected hepatocytes through a bystander mechanism as seen in the case of colorectal cancer associated with Fusobacterium nucleatum and gastric cancer related to Helicobacter pylori.

• #53 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10135776/

  The cells of origin of HCC are not clear. Experimental evidence supports the implication of transformed mature hepatocytes as the cell of origin, but also the possibility that the source is liver stem cells. […] HCC is the result of either mutations, such as those in the TERT promoter or p53 suppressor gene, or epigenetic modifications. Some of them are directly involved or activate important signaling pathways leading to HCC. […] In general, three mechanisms are implicated in the initiation and progress of HCC, namely, persistent liver inflammation, endoplasmic reticulum (ER) stress and abnormalities of cell signaling pathways. Inflammation is an important pathogenetic factor irrespective of the etiology of the liver disease that leads to HCC. […] Chronic ER stress and increased UPR activity have been implicated in the development of HCC and are present in HCC tumors irrespective of grade or stage.

• #54 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://www.mdpi.com/2227-9059/11/4/1166

  Autophagy is an important degradation process of cellular contents, leading to the recirculation of structural components of the cell and improved survival. […] The purpose of this review is to present the current views on HCC pathogenesis and the complex interplay of autophagy, apoptosis and ferroptosis in the pathophysiology and treatment of HCC. […] Inflammation is an important pathogenetic factor irrespective of the etiology of the liver disease that leads to HCC. […] Chronic ER stress and increased UPR activity have been implicated in the development of HCC and are present in HCC tumors irrespective of grade or stage. […] The abnormal activation of the oncogenic phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling is associated with HCC.

• #55 Molecular Pathogenesis of Hepatocellular Carcinoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5075835/

  Epigenetic alterations are reversible modifications at the genome level without involving changes of the DNA sequence. […] The valuable information generated by various genomic, transcriptomic and epigenetic alterations provide us with a comprehensive assessment about how these changes may affect key signaling pathways supporting the development of HCC. […] With efforts from studies pinpointing the multiple aspects of HCC pathogenesis, knowledge has been accumulating on the stochastic molecular alterations targeting different cancer hallmark events. […] The intimate relationship between tumor microenvironment and cancer metabolism has been explored in a number of studies and new data are rapidly emerging. […] In HCC, hypoxia-inducible factor (HIF)-1-induced glycolysis is associated with biological aggressiveness.

• #56 Pathophysiology of liver cirrhosis and risk correlation between immune status and the pathogenesis of hepatocellular carcinoma

  https://www.oaepublish.com/articles/2394-5079.2024.141

  The role of immune dysfunction in HCC risk stratification and screening remains underexplored, particularly in elderly and immunocompromised populations. […] The etiology and the duration of the cirrhotic process significantly influence the risk of HCC. […] Chronic liver injury, regardless of its etiology, establishes a proinflammatory microenvironment that modifies immune and stromal cell interactions within the liver. […] The inflammatory microenvironment in CLD exacerbates hepatocellular stress through various mechanisms, including mitochondrial dysfunction, epigenetic modifications, DNA damage, and chromosomal alterations. […] HCC development is driven by a combination of genetic and epigenetic alterations, chronic inflammation, and immune dysfunction. […] These molecular events synergize with immune dysfunction, promoting the escape of precancerous hepatocytes from immune surveillance and propelling the progression toward HCC.

• #57 Etiology, Mechanism and Treatment of Liver Cancer | IntechOpen

  https://www.intechopen.com/chapters/84187

  The long-term inflammation by hepatitis B or C virus, chronic alcohol consumption or and NASH, highly contribute to reprogramming of non-CSC into CSCs. […] Dysbiosis is a process in which tight junction of proteins disrupt and gut mucous layer become thinner, which leads to dysfunctional intestinal barrier. […] The gut microbial dysbiosis deteriorates the metabolism, nutrition, immunity and inflammatory status of the liver. […] The pathogenic micro-organisms antigen pass through the gut epithelium and recognized by dendritic cells, which stimulate the adaptive immune system by altering the T cells response to influence the development of HCC.

• #58 GDF15: Immunomodulatory Role in Hepatocellular Carcinoma Pathogenesis | JHC

  https://www.dovepress.com/gdf15-immunomodulatory-role-in-hepatocellular-carcinoma-pathogenesis-a-peer-reviewed-fulltext-article-JHC

  GDF15 exerts a substantial impact on various activities related to HCC, including proliferation, migration, invasion, angiogenesis, and other processes associated with carcinogenesis. […] GDF15 is found in both HSCs and HCC cells. HCC is commonly seen in people with fibrotic livers. HSCs act as fibroblasts that produce extracellular matrix (ECM) proteins and are key players in liver fibrosis. […] The study showed a significant increase in GDF15 in human HCC, with more GDF15-expressing HSCs in cancerous regions than in non-cancerous ones, indicating the role of GDF15 in promoting liver tumors. […] When the liver is damaged in MASH or MAFLD, HSCs are activated and become myofibroblast-like cells. […] Overactivation of HSCs by GDF15 can worsen liver fibrosis and possibly contribute to HCC development.

• #59 Molecular Pathogenesis of Hepatocellular Carcinoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5075835/

  CSCs or tumor-initiating cells are a subpopulation of tumor cells that possess the ability to self-renew and differentiate. […] In HCC, a recent comprehensive study provided insight on the origin of liver CSCs. […] Over the past decade, a number of liver CSC surface markers have been identified, as evidenced by the functional CSC properties. […] Dysregulation of these two pathways has also been found to be associated with the maintenance of liver CSCs. […] Since most HCCs develop from a chronic inflammatory background of the liver, it has been reasoned that CSCs can evolve, or their stemness properties are maintained from the interaction with the tumor microenvironment. […] Despite the emergence of various therapeutic modalities including chemotherapy, targeted therapy and radiotherapy in recent years, the efficacy in eradicating HCC is still unsatisfactory partially attributed to resistance to treatment conferred by liver CSCs. […] Identification of key molecular events and crucial signaling pathways provides insight to devise targeted therapies to treat this cancer.

• #60 Molecular Pathogenesis of Hepatocellular Carcinoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5075835/

  CSCs or tumor-initiating cells are a subpopulation of tumor cells that possess the ability to self-renew and differentiate. […] In HCC, a recent comprehensive study provided insight on the origin of liver CSCs. […] Over the past decade, a number of liver CSC surface markers have been identified, as evidenced by the functional CSC properties. […] Dysregulation of these two pathways has also been found to be associated with the maintenance of liver CSCs. […] Since most HCCs develop from a chronic inflammatory background of the liver, it has been reasoned that CSCs can evolve, or their stemness properties are maintained from the interaction with the tumor microenvironment. […] Despite the emergence of various therapeutic modalities including chemotherapy, targeted therapy and radiotherapy in recent years, the efficacy in eradicating HCC is still unsatisfactory partially attributed to resistance to treatment conferred by liver CSCs. […] Identification of key molecular events and crucial signaling pathways provides insight to devise targeted therapies to treat this cancer.

• #61 Etiology, Mechanism and Treatment of Liver Cancer | IntechOpen

  https://www.intechopen.com/chapters/84187

  The development of liver cancer is a multistage and branched process of morphological and genetic traits. The tumor in liver is not only associated with cellular malignancy but also linked with genome abnormality, which ultimately cause neoplastic growth. […] The hepatic-carcinogenesis emerged by two most important oncogenic events such as telomerase reverse transcriptase (TERT) activation and MYC activation. […] The epigenetic alterations include DNA hypo-methylation or hyper-methylation, chromatin remodeling, dysregulation of histone adaptation patterns, aberrant expression of micro-RNAs (miRNAs) and long noncoding RNAs (lncRNAs) are allied with HCC. […] The signaling pathways upregulate or downregulate according to etiological factors of HCC. […] The cancer stem cell (CSC) also involved in progression, aggressiveness and metastasis of HCC, by the action of several surface markers such as epithelial cell adhesion molecule (EpCAM), CD13, CD44, CD90 and CD133.

• #62 Molecular Pathogenesis of Hepatocellular Carcinoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5075835/

  CSCs or tumor-initiating cells are a subpopulation of tumor cells that possess the ability to self-renew and differentiate. […] In HCC, a recent comprehensive study provided insight on the origin of liver CSCs. […] Over the past decade, a number of liver CSC surface markers have been identified, as evidenced by the functional CSC properties. […] Dysregulation of these two pathways has also been found to be associated with the maintenance of liver CSCs. […] Since most HCCs develop from a chronic inflammatory background of the liver, it has been reasoned that CSCs can evolve, or their stemness properties are maintained from the interaction with the tumor microenvironment. […] Despite the emergence of various therapeutic modalities including chemotherapy, targeted therapy and radiotherapy in recent years, the efficacy in eradicating HCC is still unsatisfactory partially attributed to resistance to treatment conferred by liver CSCs. […] Identification of key molecular events and crucial signaling pathways provides insight to devise targeted therapies to treat this cancer.

• #63 Etiology, Mechanism and Treatment of Liver Cancer | IntechOpen

  https://www.intechopen.com/chapters/84187

  The long-term inflammation by hepatitis B or C virus, chronic alcohol consumption or and NASH, highly contribute to reprogramming of non-CSC into CSCs. […] Dysbiosis is a process in which tight junction of proteins disrupt and gut mucous layer become thinner, which leads to dysfunctional intestinal barrier. […] The gut microbial dysbiosis deteriorates the metabolism, nutrition, immunity and inflammatory status of the liver. […] The pathogenic micro-organisms antigen pass through the gut epithelium and recognized by dendritic cells, which stimulate the adaptive immune system by altering the T cells response to influence the development of HCC.

• #64 Molecular Pathogenesis of Hepatocellular Carcinoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5075835/

  CSCs or tumor-initiating cells are a subpopulation of tumor cells that possess the ability to self-renew and differentiate. […] In HCC, a recent comprehensive study provided insight on the origin of liver CSCs. […] Over the past decade, a number of liver CSC surface markers have been identified, as evidenced by the functional CSC properties. […] Dysregulation of these two pathways has also been found to be associated with the maintenance of liver CSCs. […] Since most HCCs develop from a chronic inflammatory background of the liver, it has been reasoned that CSCs can evolve, or their stemness properties are maintained from the interaction with the tumor microenvironment. […] Despite the emergence of various therapeutic modalities including chemotherapy, targeted therapy and radiotherapy in recent years, the efficacy in eradicating HCC is still unsatisfactory partially attributed to resistance to treatment conferred by liver CSCs. […] Identification of key molecular events and crucial signaling pathways provides insight to devise targeted therapies to treat this cancer.

• #65 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10135776/

  The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. […] The development of HCC is associated with some form of cellular death, which may be either programmed (PCD) (such as apoptosis, necroptosis and autophagy-dependent cell death) or non-programmable (such as pyroptosis and necrosis). Apoptosis is probably the commonest cause of PCD.

• #66 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://www.mdpi.com/2227-9059/11/4/1166

  The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. […] The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. […] Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. […] The development of HCC is associated with some form of cellular death, which may be either programmed (PCD) (such as apoptosis, necroptosis and autophagy-dependent cell death) or non-programmable (such as pyroptosis and necrosis). […] Apoptosis is probably the commonest cause of PCD.

• #67 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://www.mdpi.com/2227-9059/11/4/1166

  Autophagy is an important degradation process of cellular contents, leading to the recirculation of structural components of the cell and improved survival. […] The purpose of this review is to present the current views on HCC pathogenesis and the complex interplay of autophagy, apoptosis and ferroptosis in the pathophysiology and treatment of HCC. […] Inflammation is an important pathogenetic factor irrespective of the etiology of the liver disease that leads to HCC. […] Chronic ER stress and increased UPR activity have been implicated in the development of HCC and are present in HCC tumors irrespective of grade or stage. […] The abnormal activation of the oncogenic phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling is associated with HCC.

• #68 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://www.mdpi.com/2227-9059/11/4/1166

  The deregulation of Wnt/β-catenin signaling is critical in human HCC. […] The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. […] Autophagy is implicated in the initiation and progression of HCC in many ways. […] The activation of the Wnt/β-catenin pathway favors the development of HCC. […] The mechanisms of HCC induction and progression in HCV infection have been recently reviewed in detail. […] The role of ferroptosis in HCC initiation and progression has been extensively reviewed. […] The manipulation of either autophagy or apoptosis will improve the treatment outcomes of a difficult-to-treat tumor.

• #69 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10135776/

  The abnormal activation of the oncogenic phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling is associated with HCC. […] The deregulation of Wnt/-catenin signaling is critical in human HCC. […] The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. […] Autophagy is implicated in the initiation and progression of HCC in many ways. It is closely associated with inflammation, which is a critical factor in HCC development. […] The activation of the Wnt/-catenin pathway favors the development of HCC, as previously mentioned. […] The activation of autophagy may lead to the induction of apoptosis and the inhibition of the growth of hepatoma cells.

• #70 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10135776/

  The interplay between autophagy and apoptosis may be implicated in the pathogenesis of NASH and ALD. […] The mechanisms of HCC induction and progression in HCV infection have been recently reviewed in detail. […] The role of ferroptosis in HCC initiation and progression has been extensively reviewed. […] Autophagy and apoptosis are two forms of regulated cell death. They are critically implicated in the regulation of HCC biology. Autophagy is interrelated with apoptosis and chemotherapy in HCC. Generally, the induction of autophagy inhibits caspase-dependent apoptosis, and the induction of apoptosis-associated caspase activation blocks the autophagic process. However, autophagy may also induce apoptosis.

• #71 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10135776/

  The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. […] The development of HCC is associated with some form of cellular death, which may be either programmed (PCD) (such as apoptosis, necroptosis and autophagy-dependent cell death) or non-programmable (such as pyroptosis and necrosis). Apoptosis is probably the commonest cause of PCD.

• #72 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://www.mdpi.com/2227-9059/11/4/1166

  The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. […] The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. […] Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. […] The development of HCC is associated with some form of cellular death, which may be either programmed (PCD) (such as apoptosis, necroptosis and autophagy-dependent cell death) or non-programmable (such as pyroptosis and necrosis). […] Apoptosis is probably the commonest cause of PCD.

• #73 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10135776/

  The interplay between autophagy and apoptosis may be implicated in the pathogenesis of NASH and ALD. […] The mechanisms of HCC induction and progression in HCV infection have been recently reviewed in detail. […] The role of ferroptosis in HCC initiation and progression has been extensively reviewed. […] Autophagy and apoptosis are two forms of regulated cell death. They are critically implicated in the regulation of HCC biology. Autophagy is interrelated with apoptosis and chemotherapy in HCC. Generally, the induction of autophagy inhibits caspase-dependent apoptosis, and the induction of apoptosis-associated caspase activation blocks the autophagic process. However, autophagy may also induce apoptosis.

• #74 Pyroptosis is involved in the pathogenesis of human hepatocellular carcinoma | Oncotarget

  https://www.oncotarget.com/article/12384/

  Pyroptosis is a caspase-1 dependent programmed cell death, which is involved in the pathologic process of several kinds of cancers. […] However, the role of pyroptosis in human hepatocellular carcinoma (HCC) remains largely unknown. The aim of this study was to investigate the involvement of pyroptosis in the pathogenesis of HCC. Our study showed that pyroptosis was inhibited in HCC tissues and cells. […] Conclusively, pyroptosis is involved in the pathogenesis of HCC, and may be a new neoplastic target for the treatment of HCC.

• #75 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10135776/

  The interplay between autophagy and apoptosis may be implicated in the pathogenesis of NASH and ALD. […] The mechanisms of HCC induction and progression in HCV infection have been recently reviewed in detail. […] The role of ferroptosis in HCC initiation and progression has been extensively reviewed. […] Autophagy and apoptosis are two forms of regulated cell death. They are critically implicated in the regulation of HCC biology. Autophagy is interrelated with apoptosis and chemotherapy in HCC. Generally, the induction of autophagy inhibits caspase-dependent apoptosis, and the induction of apoptosis-associated caspase activation blocks the autophagic process. However, autophagy may also induce apoptosis.

• #76 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://www.mdpi.com/2227-9059/11/4/1166

  The deregulation of Wnt/β-catenin signaling is critical in human HCC. […] The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. […] Autophagy is implicated in the initiation and progression of HCC in many ways. […] The activation of the Wnt/β-catenin pathway favors the development of HCC. […] The mechanisms of HCC induction and progression in HCV infection have been recently reviewed in detail. […] The role of ferroptosis in HCC initiation and progression has been extensively reviewed. […] The manipulation of either autophagy or apoptosis will improve the treatment outcomes of a difficult-to-treat tumor.

• #77

  https://link.springer.com/article/10.1007/s10555-023-10084-4

  Hepatocellular carcinoma (HCC) is a common malignancy and one of the leading causes of cancer-related death. […] The biological process of HCC is complex, with multiple factors leading to the broken of the balance of inactivation and activation of tumor suppressor genes and oncogenes, the abnormal activation of molecular signaling pathways, the differentiation of HCC cells, and the regulation of angiogenesis. […] Correct understanding of the molecular mechanism of HCC occurrence is key to seeking effective targeted therapy. […] Here, we explore the molecular mechanism that are associated with HCC development, summarize targeted therapies for HCC, and discuss potential biomarkers that may drive therapies. […] The complex pathogenesis of HCC has inspired researchers to explore a variety of biomolecular targeted therapeutics targeting specific targets.

• #78 Genes & Cancer | Pathogenesis to management of hepatocellular carcinoma

  https://www.genesandcancer.com/article/226/

  Hepatocellular carcinoma (HCC) is the most common primary liver cancer whose incidence continues to rise in many parts of the world due to a concomitant rise in many associated risk factors, such as alcohol use and obesity. […] This is because HCC is a cancer with significant complexities, including substantial clinical, histopathologic, and genomic heterogeneity. […] However, the scientific community has made a major effort to better characterize HCC in those aspects via utilizing tissue sampling and histological classification, whole genome sequencing, and developing viable animal models. […] These efforts ultimately aim to develop clinically relevant biomarkers and discover molecular targets for new therapies. […] This review will focus on the link between characterizing the pathogenesis of HCC with current and future HCC management.

• #79 Genes & Cancer | Pathogenesis to management of hepatocellular carcinoma

  https://www.genesandcancer.com/article/226/text/

  Epigenetic alterations include changes in methylation, chromatin remodeling, and micro-RNAs. […] Animal models allow for the integration of the genomic and molecular characterization of human HCC samples in a way that permits for the discovery and testing of biomarkers and novel HCC therapies. […] The NASH-HCC model is MUP-uPA mice fed a high-fat diet (HFD), resulting in steatohepatitis resembling human NASH. […] The immune component of the HCC microenvironment has been of great interest with the recent approval of immunotherapies, such as immune checkpoint inhibitors, for advanced stage HCC. […] The aberrant activity of the TGF- pathway is involved in nearly 40% of HCCs, and deficiency of this pathway is observed in the cancer stem cell signature of HCC. […] While personalized medicine has become a practical reality in other cancers, HCC has been difficult to target with specific treatments based on molecular profiling. […] One of the main reasons for targeted therapies failure is tumor heterogeneity (inter and intra-subject). […] A challenge to developing therapies is that somatic mutations occur in genes whose products are not easily or safely druggable, such as mutated forms of TERT, TP53, CTNNB1, and MYC.

• #80 Hepatocellular carcinoma: Molecular pathogenesis and therapeutic advances

  https://repositori.upf.edu/items/27cb7ca4-6827-431a-b68d-901e2804ef4f

  Hepatocellular carcinoma (HCC), the most common form of liver cancer, continues to be a serious medical problem with poor prognosis, without major therapeutic improvement for years and increasing incidence. […] Although infections by hepatitis B virus and hepatitis C virus remain principal factors for HCC development, the rise of non-alcoholic steatohepatitis from diabetes mellitus or metabolic syndrome is impeding HCC decline. […] Knowledge of specific molecular mechanisms, based on the etiology and the HCC microenvironment that influence tumor growth and immune control, will be crucial for physician decision-making among a variety of drugs to prescribe. […] Consequently, research to provide scientific data for the evidence-based management of liver cancer is guaranteed in the coming years and discussed here.

• #81 Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

  https://www.mdpi.com/2227-9059/11/4/1166

  The deregulation of Wnt/β-catenin signaling is critical in human HCC. […] The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. […] Autophagy is implicated in the initiation and progression of HCC in many ways. […] The activation of the Wnt/β-catenin pathway favors the development of HCC. […] The mechanisms of HCC induction and progression in HCV infection have been recently reviewed in detail. […] The role of ferroptosis in HCC initiation and progression has been extensively reviewed. […] The manipulation of either autophagy or apoptosis will improve the treatment outcomes of a difficult-to-treat tumor.

• #82 Super-enhancers in hepatocellular carcinoma: regulatory mechanism and therapeutic targets | Cancer Cell International | Full Text

  https://cancerci.biomedcentral.com/articles/10.1186/s12935-024-03599-5

  There is mounting evidence suggesting that SEs exert pivotal control over central hallmarks of cancer, including abnormal cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). […] Together, SEs accelerate cell proliferation, migration, invasion, and EMT mainly through genes such as SPHK1, AJUBA, QKI and SPIDR, promoting the malignant progression of hepatocellular carcinoma. […] In conclusion, SE promotes the transcriptional silencing of TSGs through SIRT7-mediated epigenetic modification, indicating that it is particularly important to study the potential regulation of SE on tumor suppressor genes. […] Super-enhancers (SEs) have emerged as promising therapeutic targets in hepatocellular carcinoma (HCC). […] Here we concluded the potential function and the inhibitors of three key components of SEs, which may provide new prospects for optimum treatment of HCC by targeting SEs.

• #83 GDF15: Immunomodulatory Role in Hepatocellular Carcinoma Pathogenesis | JHC

  https://www.dovepress.com/gdf15-immunomodulatory-role-in-hepatocellular-carcinoma-pathogenesis-a-peer-reviewed-fulltext-article-JHC

  GDF15 promotes angiogenesis by activating Src and its downstream signals. […] GDF15 significantly increases in HCC cells when exposed to chemotherapy or hypoxia. […] GDF15 plays a role in promoting suppressive functionality of immune cells as illustrated in Figure 2. […] The harmful impact of GDF15 on HCC involves its immunosuppressive role through Treg cells. […] GDF15 inhibits DC maturation and function, impairing tumor-specific immune responses. […] Tumor-derived GDF15 facilitates HCC development by inhibiting the TAK1 to NF-B signaling, reducing TNF and NO synthesis, and thus inhibiting macrophage activity. […] GDF15 helps colon cancer cells evade NK cell surveillance by regulating their activity, in which GDF15 expression is regulated by acetylation. […] Given the critical role of GDF15 in HCC, inhibiting the function or expression of GDF15 may become an effective therapeutic strategy. […] Therefore, GDF15 provides a new avenue for HCC treatment.

• #84 Molecular mechanism of hepatocellular carcinoma

  https://www.oaepublish.com/articles/2394-5079.2018.23

  The major risk factors for HCC include hepatitis B and C virus infection, alcohol, NAFLD, chemical toxins and hereditary disorders. […] During hepatocarcinogenesis, numerous factors, such as oxidative stress, inflammation, hormone systems, hypoxia and immunity, are dysregulated, leading to the development of HCC. […] Emerging scRNA-seq technology is a powerful tool for defining sub-populations of cells within a heterogeneous bulk of tumor tissue and has been a breakthrough that has the potential to unveil the molecular mechanisms of HCC.

• #85 Pathogenesis to management of hepatocellular carcinoma

  https://medicalxpress.com/news/2023-01-pathogenesis-hepatocellular-carcinoma.html

  A new review was published in Genes & Cancer on December 13, 2022, entitled, „Pathogenesis to management of hepatocellular carcinoma.” In this review, researchers from multiple universities and medical centers across the U.S. discussed hepatocellular carcinoma (HCC)—the most common primary liver cancer, whose incidence continues to rise in many parts of the world due to a concomitant rise in many associated risk factors, such as alcohol use and obesity. […] Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third most common cause of cancer death. Although early-stage HCC can be potentially curable through liver resection, liver-directed therapies, or transplantation, patients usually present with intermediate to advanced disease, which continues to be associated with a poor prognosis. This is because HCC is a cancer with significant complexities, including substantial clinical, histopathologic, and genomic heterogeneity. However, the scientific community has made a major effort to better characterize HCC in those aspects via utilizing tissue sampling and histological classification, whole genome sequencing, and developing viable animal models.

• #86 Introductory Chapter: Etiology and Pathogenesis of Hepatocellular Carcinoma | IntechOpen

  https://www.intechopen.com/chapters/61816

  The mechanism by which obesity leads to cancer is unclear; insulin resistance and its subsequent inflammatory cascade, and insulin growth factor (IGF)-1 seem to be implicated. […] Since the incidence of obesity and diabetes is in a continuous growth in the world, Kelly, and co. study demonstrated a direct established relationship between diabetes and HCC risk. […] HCC is a complex pathogenesis link with various risk factors. Liver cirrhosis is, unsurprisingly, an important risk factor for HCC development, regardless of the cause, whereas chronic HBV and HCV infections are the most significant developing factors for liver cancer worldwide.

• #87 Hepatocellular carcinoma: Molecular pathogenesis and therapeutic advances

  https://repositori.upf.edu/items/27cb7ca4-6827-431a-b68d-901e2804ef4f

  Hepatocellular carcinoma (HCC), the most common form of liver cancer, continues to be a serious medical problem with poor prognosis, without major therapeutic improvement for years and increasing incidence. […] Although infections by hepatitis B virus and hepatitis C virus remain principal factors for HCC development, the rise of non-alcoholic steatohepatitis from diabetes mellitus or metabolic syndrome is impeding HCC decline. […] Knowledge of specific molecular mechanisms, based on the etiology and the HCC microenvironment that influence tumor growth and immune control, will be crucial for physician decision-making among a variety of drugs to prescribe. […] Consequently, research to provide scientific data for the evidence-based management of liver cancer is guaranteed in the coming years and discussed here.

• #88 Genes & Cancer | Pathogenesis to management of hepatocellular carcinoma

  https://www.genesandcancer.com/article/226/text/

  Epigenetic alterations include changes in methylation, chromatin remodeling, and micro-RNAs. […] Animal models allow for the integration of the genomic and molecular characterization of human HCC samples in a way that permits for the discovery and testing of biomarkers and novel HCC therapies. […] The NASH-HCC model is MUP-uPA mice fed a high-fat diet (HFD), resulting in steatohepatitis resembling human NASH. […] The immune component of the HCC microenvironment has been of great interest with the recent approval of immunotherapies, such as immune checkpoint inhibitors, for advanced stage HCC. […] The aberrant activity of the TGF- pathway is involved in nearly 40% of HCCs, and deficiency of this pathway is observed in the cancer stem cell signature of HCC. […] While personalized medicine has become a practical reality in other cancers, HCC has been difficult to target with specific treatments based on molecular profiling. […] One of the main reasons for targeted therapies failure is tumor heterogeneity (inter and intra-subject). […] A challenge to developing therapies is that somatic mutations occur in genes whose products are not easily or safely druggable, such as mutated forms of TERT, TP53, CTNNB1, and MYC.

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