Materiały źródłowe

• #1 Cervical Cancer – Gynecology and Obstetrics – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/gynecology-and-obstetrics/gynecologic-tumors/cervical-cancer

  Cervical cancer is usually squamous cell carcinoma; adenocarcinoma is less common. The cause of most cervical cancers is human papillomavirus (HPV) infection. The precursor to cervical cancer is cervical intraepithelial neoplasia (CIN). The great majority of cases of CIN and invasive cervical cancer are caused by persistent infection with human papillomavirus (HPV), transmitted mainly through sexual activity. Most (70%) of precancerous and invasive disease can be directly attributed to HPV types 16 or 18; however, 99% of cervical cancer specimens contain DNA from one of more than 14 high-risk HPV genotypes. The incidence of cervical cancer has decreased steadily over the past several decades because of HPV vaccination, cervical cancer screening, and treatment of CIN. […] About 80 to 85% of all cervical cancers are squamous cell carcinoma; most of the rest are adenocarcinomas. Invasive cervical cancer usually spreads by direct extension into surrounding tissues or via the lymphatics to the pelvic and para-aortic lymph nodes. Hematogenous spread is possible but rare. […] If cervical cancer spreads to the pelvic or para-aortic lymph nodes, the prognosis is worse, and the location and size of the radiation therapy field is affected.

• #1 Cervical cancer – Wikipedia

  https://en.wikipedia.org/wiki/Cervical_cancer

  Cervical cancer is a cancer arising from the cervix or in any layer of the wall of the cervix. It is due to the abnormal growth of cells that can invade or spread to other parts of the body. Virtually all cervical cancer cases (99%) are linked to genital human papillomavirus infection (HPV); most who have had HPV infections, however, do not develop cervical cancer. HPV 16 and 18 strains are responsible for approximately 70% of cervical cancer cases globally and nearly 50% of high grade cervical pre-cancers. Cervical cancer typically develops from precancerous changes called cervical intraepithelial neoplasia over 10 to 20 years. High risk HPV viral subtypes can integrate their DNA into the host genome and induce transcription of the viral cancer causing proteins E6 and E7. E6 degrades the tumor suppressing protein p53 and E7 degrades and inactivates the tumor suppressing protein pRb. The loss of p53 and pRb leads to increased blood vessel growth feeding tumors (via vascular endothelial growth factor(VEGF) over-expression), loss of tumor cell suppression and cell cycle regulation disruptions all of which can lead to cervical cancer.

• #2 Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis – UpToDate

  https://www.uptodate.com/contents/invasive-cervical-cancer-epidemiology-risk-factors-clinical-manifestations-and-diagnosis

  Human papillomavirus (HPV) is central to the development of cervical neoplasia and can be detected in 99.7 percent of cervical cancers. […] The most common histologic types of cervical cancer are squamous cell (70 percent of cervical cancers) and adenocarcinoma (25 percent).

• #2 Molecular aspects of cervical cancer: a pathogenesis update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10985348/

  The main etiologic factor for CC development is a persistent infection with high-risk (HR) human papillomavirus (HPV), responsible for almost 100% of all CC cases. However, some studies report that between 5 and 8% of CC cases are HPV-negative; significantly, the majority are adenocarcinomas. […] HPV infection targets the cervix transformation zone, a region susceptible to the development of premalignant cervical lesions and, potentially, cancer. Initially, these lesions were categorized based on their severity and extent of atypical epithelial tissue changes, leading to the classification of cervical intraepithelial neoplasia (CIN) grades I, II, and III, as well as carcinoma in situ (CC). […] The determinants of HR-HPV persistent infections are not precise. Still, they may be related to the inability of the host to mount an adequate innate immune response and a robust cell-mediated immunity, as well as the ability of the viral proteins to evade immune detection.

• #3 Key Molecular Events in Cervical Cancer Development

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6681523/

  Progression of HPV infected epithelial cells to invasive cancer is a long-term process associated with the accumulation of DNA alterations in host cell genes. These alterations involve both epigenetic and genetic changes in oncogenes and tumour suppressor genes. HPV enters the host basal squamous cells through a micro-wound or abrasion. The virus must be able to integrate into the host cell to initiate the infection, where a series of genetic events occur within the basal epithelial cells directly enabling viral replication. […] The HPV oncoproteins, mainly E6 and E7, play a major role in the alteration of host cellular function. HPVs overexpress E6 and E7 oncoproteins to disrupt the normal function of tumour suppressor genes in the host. Upon integration, the viral proteins begin to damage the host cells. Host cells have evolved a special mechanism to repair the damage inflicted upon their DNA via DNA damage response.

• #4

  https://link.springer.com/article/10.1007/s13337-022-00768-w

  Cervical cancer is marked by the uncontrolled proliferation and division of cells making up the cervix. […] In most cases, persistent infection with highly infectious types of human papillomavirus (HPV) such as HPV 16 and 18 is believed to be the cause of the disease. The HPV virus is primarily reported to invade cervical epithelial cells and then goes through a non-viremic infection cycle under the influence of various potent viral oncogenic proteins, namely E6 and E7. Among several other risk factors, increased oxidative stress, hyperactivation of inflammatory pathways, and immunological factors play a key role in cervical cancer pathogenesis. […] The review discussed the role of HPV in the development of cervical cancer and its pathogenesis. Further, summarized the potential therapeutic biomarkers for the prevention and treatment of cervical cancer.

• #5 Cervical Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/253513-overview

  Human papillomavirus (HPV) infection must be present for cervical cancer to occur. […] HPV infection occurs in a high percentage of sexually active women. However, approximately 90% of HPV infections clear on their own within months to a few years and with no sequelae, although cytology reports in the 2 years following infection may show a low-grade squamous intraepithelial lesion. […] On average, only 5% of HPV infections will result in the development of CIN grade 2 or 3 lesions (the recognized cervical cancer precursor) within 3 years of infection. Only 20% of CIN 3 lesions progress to invasive cervical cancer within 5 years, and only 40% of CIN 3 lesions progress to invasive cervical cancer with 30 years. […] Because only a small proportion of HPV infections progress to cancer, other factors must be involved in the process of carcinogenesis. The following factors have been postulated to influence the development of CIN 3 lesions:

• #6 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2

  Integration of HPV DNA into the host cell genome is a key event in HPV-mediated carcinogenesis leading to aberrant proliferation and malignant progression. Integration impacts the host genome by amplification of oncogenes and disruption of tumor suppressor genes as well as driving inter- and intra-chromosomal rearrangements. […] The early genes E6 and E7 play an essential role in HPV-induced carcinogenesis by interfering with two essential tumor suppressor genes p53 and pRb that regulate normal cellular proliferation. The interaction of E7 with pRb protein causes its degradation and aberrant initiation of S-phase and release of E2F transcription factor that triggers the expression of cyclins and other S-phase regulators. The mechanism of E6/E7-induced transformation is not confined exclusively to the degradation of the key cellular guardians pRb and p53. E7 also associates with other proteins involved in cell proliferation, including histone deacetylases, components of the AP1 transcription complex and the cyclin-dependent kinase inhibitors p21 and p27. At the same time, E6 protein targets p53 for proteasomal degradation and causes inhibition of apoptosis and DNA repair which is an integral component of the HPV life cycle.

• #7 Molecular aspects of cervical cancer: a pathogenesis update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10985348/

  It is proposed that during persistent HPV infections, mutations and chromosomal abnormalities accumulate over time, promoting integration of the viral genome into the cellular genome and contributing to cancer progression. […] In many cases of CC, the viral genome integration frequently occurs in the E1 and E2 genes, affecting their expression and leading to the uncontrolled expression of the oncogenes E6 and E7. The maintenance of the tumor phenotype requires the continuous expression of the E6 and E7 oncogenes. […] Gene loss, duplication, or overexpression is a common feature of the HPV genome in CC. This is due to deletions, errors during the replication process, or mutations in genes of the HPV genome that increase the expression of the HPV gene products. HPV gene diversity and duplication have been reported in CC. Overexpression of E6 and E7 after HPV integration is considered the trigger for malignant progression due to cell cycle disruption and induction of genome instability; also, multiple HPV integration events have been associated with poor prognosis. Alterations that occur in the host genome due to the integration of HPV are fundamental in the development of CC.

• #8 Molecular aspects of cervical cancer: a pathogenesis update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10985348/

  It is proposed that during persistent HPV infections, mutations and chromosomal abnormalities accumulate over time, promoting integration of the viral genome into the cellular genome and contributing to cancer progression. […] In many cases of CC, the viral genome integration frequently occurs in the E1 and E2 genes, affecting their expression and leading to the uncontrolled expression of the oncogenes E6 and E7. The maintenance of the tumor phenotype requires the continuous expression of the E6 and E7 oncogenes. […] Gene loss, duplication, or overexpression is a common feature of the HPV genome in CC. This is due to deletions, errors during the replication process, or mutations in genes of the HPV genome that increase the expression of the HPV gene products. HPV gene diversity and duplication have been reported in CC. Overexpression of E6 and E7 after HPV integration is considered the trigger for malignant progression due to cell cycle disruption and induction of genome instability; also, multiple HPV integration events have been associated with poor prognosis. Alterations that occur in the host genome due to the integration of HPV are fundamental in the development of CC.

• #9 Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism | Nature Genetics

  https://www.nature.com/articles/ng.3178

  Human papillomavirus (HPV) integration is a key genetic event in cervical carcinogenesis. […] Moreover, microhomologous sequence between the human and HPV genomes was significantly enriched near integration breakpoints, indicating that fusion between viral and human DNA may have occurred by microhomology-mediated DNA repair pathways. […] Our data provide insights into HPV integration-driven cervical carcinogenesis.

• #10 Molecular aspects of cervical cancer: a pathogenesis update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10985348/

  It is proposed that during persistent HPV infections, mutations and chromosomal abnormalities accumulate over time, promoting integration of the viral genome into the cellular genome and contributing to cancer progression. […] In many cases of CC, the viral genome integration frequently occurs in the E1 and E2 genes, affecting their expression and leading to the uncontrolled expression of the oncogenes E6 and E7. The maintenance of the tumor phenotype requires the continuous expression of the E6 and E7 oncogenes. […] Gene loss, duplication, or overexpression is a common feature of the HPV genome in CC. This is due to deletions, errors during the replication process, or mutations in genes of the HPV genome that increase the expression of the HPV gene products. HPV gene diversity and duplication have been reported in CC. Overexpression of E6 and E7 after HPV integration is considered the trigger for malignant progression due to cell cycle disruption and induction of genome instability; also, multiple HPV integration events have been associated with poor prognosis. Alterations that occur in the host genome due to the integration of HPV are fundamental in the development of CC.

• #11 Molecular aspects of cervical cancer: a pathogenesis update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10985348/

  It is proposed that during persistent HPV infections, mutations and chromosomal abnormalities accumulate over time, promoting integration of the viral genome into the cellular genome and contributing to cancer progression. […] In many cases of CC, the viral genome integration frequently occurs in the E1 and E2 genes, affecting their expression and leading to the uncontrolled expression of the oncogenes E6 and E7. The maintenance of the tumor phenotype requires the continuous expression of the E6 and E7 oncogenes. […] Gene loss, duplication, or overexpression is a common feature of the HPV genome in CC. This is due to deletions, errors during the replication process, or mutations in genes of the HPV genome that increase the expression of the HPV gene products. HPV gene diversity and duplication have been reported in CC. Overexpression of E6 and E7 after HPV integration is considered the trigger for malignant progression due to cell cycle disruption and induction of genome instability; also, multiple HPV integration events have been associated with poor prognosis. Alterations that occur in the host genome due to the integration of HPV are fundamental in the development of CC.

• #12 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2

  Integration of HPV DNA into the host cell genome is a key event in HPV-mediated carcinogenesis leading to aberrant proliferation and malignant progression. Integration impacts the host genome by amplification of oncogenes and disruption of tumor suppressor genes as well as driving inter- and intra-chromosomal rearrangements. […] The early genes E6 and E7 play an essential role in HPV-induced carcinogenesis by interfering with two essential tumor suppressor genes p53 and pRb that regulate normal cellular proliferation. The interaction of E7 with pRb protein causes its degradation and aberrant initiation of S-phase and release of E2F transcription factor that triggers the expression of cyclins and other S-phase regulators. The mechanism of E6/E7-induced transformation is not confined exclusively to the degradation of the key cellular guardians pRb and p53. E7 also associates with other proteins involved in cell proliferation, including histone deacetylases, components of the AP1 transcription complex and the cyclin-dependent kinase inhibitors p21 and p27. At the same time, E6 protein targets p53 for proteasomal degradation and causes inhibition of apoptosis and DNA repair which is an integral component of the HPV life cycle.

• #13 Cervical Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/253513-overview

  Upon integration into the human genome, the linearization of high-risk HPV DNA places the E6 and E7 genes in a position of enhanced replication. E7 binds and inactivates the Rb protein while E6 binds p53 and directs its degradation, and the functional loss of the TP53 and RB genes leads to resistance to apoptosis, causing uncensored cell growth after DNA damage. This ultimately results in progression to malignancy. […] The role of HIV infection in the pathogenesis of cervical cancer is not fully understood. However, HIV infection is known to suppress the already low level of immune recognition of HPV infection, allowing HPV to cause more damage than it would in immunocompetent women.

• #14 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2

  Integration of HPV DNA into the host cell genome is a key event in HPV-mediated carcinogenesis leading to aberrant proliferation and malignant progression. Integration impacts the host genome by amplification of oncogenes and disruption of tumor suppressor genes as well as driving inter- and intra-chromosomal rearrangements. […] The early genes E6 and E7 play an essential role in HPV-induced carcinogenesis by interfering with two essential tumor suppressor genes p53 and pRb that regulate normal cellular proliferation. The interaction of E7 with pRb protein causes its degradation and aberrant initiation of S-phase and release of E2F transcription factor that triggers the expression of cyclins and other S-phase regulators. The mechanism of E6/E7-induced transformation is not confined exclusively to the degradation of the key cellular guardians pRb and p53. E7 also associates with other proteins involved in cell proliferation, including histone deacetylases, components of the AP1 transcription complex and the cyclin-dependent kinase inhibitors p21 and p27. At the same time, E6 protein targets p53 for proteasomal degradation and causes inhibition of apoptosis and DNA repair which is an integral component of the HPV life cycle.

• #15 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2

  Integration typically results in the increased expression and stability of transcripts encoding the viral oncogenes E6 and E7, which are known to inactivate and/or accelerate the degradation of numerous cellular proteins, including retinoblastoma protein (E7) and p53 (E6). The site of integration is distributed throughout the genome as chromosomal fragile sites where DNA double strand breaks fail to repair. Integration starts with DNA damage, induced either by oxidative stress or HPV protein and the subsequent steps are driven by the DNA damage responses. […] The viral oncoproteins E6 and E7 are known to induce DNA damage, centrosome abnormalities and chromosomal segregation defects, thereby leading to chromosomal instability. High-risk E6 has the ability to activate the catalytic subunit of telomerase, which adds hexamer repeats to the telomeric ends of chromosomes. HPV16 E6 associates with E6AP, to promote the degradation of the transcriptional repressor NFX1-91, and consequently activate hTERT transcription; this repressor has also a role in HPV16 E6 activation of the oncogenic transcription factor NF-B.

• #16 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2

  Integration typically results in the increased expression and stability of transcripts encoding the viral oncogenes E6 and E7, which are known to inactivate and/or accelerate the degradation of numerous cellular proteins, including retinoblastoma protein (E7) and p53 (E6). The site of integration is distributed throughout the genome as chromosomal fragile sites where DNA double strand breaks fail to repair. Integration starts with DNA damage, induced either by oxidative stress or HPV protein and the subsequent steps are driven by the DNA damage responses. […] The viral oncoproteins E6 and E7 are known to induce DNA damage, centrosome abnormalities and chromosomal segregation defects, thereby leading to chromosomal instability. High-risk E6 has the ability to activate the catalytic subunit of telomerase, which adds hexamer repeats to the telomeric ends of chromosomes. HPV16 E6 associates with E6AP, to promote the degradation of the transcriptional repressor NFX1-91, and consequently activate hTERT transcription; this repressor has also a role in HPV16 E6 activation of the oncogenic transcription factor NF-B.

• #17 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis

  https://www.mdpi.com/2076-0817/12/12/1380

  E7 activates the cell cycle in differentiating infected cells through interactions with pRb (retinoblastoma tumor suppressor protein) and other proteins p107 and p130 (called pocket proteins) via the sequence LXCXE in CR2 sequences. […] The E7 oncoprotein also controls DNA methylation by regulating cell propagation pathways; thus, epigenetic alterations occur via the Rb family of tumor-suppressor proteins. […] In HPV-infected cells, the E6 protein primarily represents the neoplastic effect abrogation of p53 depending on ubiquitin. […] The binding of E6 to p53 depends on E6-associated protein (E6AP). […] HPV can use the evasion process to escape the immune response. […] HPV uses a variety of immune evasion mechanisms to suppress immune responses and promote cancer progression. […] HPV can show an immune escape strategy not only by hiding itself from recognition by immune cells by downregulating viral antigens, but also by disturbing the expression of immune response proteins, which further encourages prolonged viral persistence. […] HPV can acquire all these strategies to evade an effective immune response, which may eventually support the prolonged persistence of HPV infection and cervical cancer progression.

• #18 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis

  https://www.mdpi.com/2076-0817/12/12/1380

  E7 activates the cell cycle in differentiating infected cells through interactions with pRb (retinoblastoma tumor suppressor protein) and other proteins p107 and p130 (called pocket proteins) via the sequence LXCXE in CR2 sequences. […] The E7 oncoprotein also controls DNA methylation by regulating cell propagation pathways; thus, epigenetic alterations occur via the Rb family of tumor-suppressor proteins. […] In HPV-infected cells, the E6 protein primarily represents the neoplastic effect abrogation of p53 depending on ubiquitin. […] The binding of E6 to p53 depends on E6-associated protein (E6AP). […] HPV can use the evasion process to escape the immune response. […] HPV uses a variety of immune evasion mechanisms to suppress immune responses and promote cancer progression. […] HPV can show an immune escape strategy not only by hiding itself from recognition by immune cells by downregulating viral antigens, but also by disturbing the expression of immune response proteins, which further encourages prolonged viral persistence. […] HPV can acquire all these strategies to evade an effective immune response, which may eventually support the prolonged persistence of HPV infection and cervical cancer progression.

• #19 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2

  In addition to genetic alterations, it has become evident that oncogenomic processes can be profoundly influenced by epigenetic mechanisms. Epigenetic alterations are often found early in tumorigenesis and are likely to be key initiating events in certain cancers. In addition to tumor initiation, epigenetic events also contribute to tumor progression. A number of epigenetic alterations have been identified that occur in both the HPV and the cellular genome, including DNA hypomethylation, hypermethylation of tumor suppressor genes, histone modifications, and alterations in ncRNAs. […] The earliest and most common molecular changes in the multistep carcinogenesis process is DNA methylation. In normal cells, DNA methylation is involved in the regulation of gene expression, including chromatin organization and genomic imprinting. In contrast, global DNA hypomethylation in repetitive regions and hypermethylation in CpG islands of tumor suppressor gene promoters are observed in tumors, and increase in the activity of DNA methyltransferases. These alterations are also observed in HPV-induced carcinogenesis. HPV E7 binds to DNMT1 and stimulates its activity, and activates transcription of DNMT1 through the pRB/E2F pathway, while HPV E6 upregulates DNMT1 by suppression of p53. Increased expression of DNMT3A and 3B has also been observed in HPV-positive cells. Aberrant methylation occurs frequently in cervical cancer, leading to silencing of gene expression, activation of oncogenes and transposable elements, loss of imprinting, and inactivation of tumor suppressor genes.

• #20 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2

  In addition to genetic alterations, it has become evident that oncogenomic processes can be profoundly influenced by epigenetic mechanisms. Epigenetic alterations are often found early in tumorigenesis and are likely to be key initiating events in certain cancers. In addition to tumor initiation, epigenetic events also contribute to tumor progression. A number of epigenetic alterations have been identified that occur in both the HPV and the cellular genome, including DNA hypomethylation, hypermethylation of tumor suppressor genes, histone modifications, and alterations in ncRNAs. […] The earliest and most common molecular changes in the multistep carcinogenesis process is DNA methylation. In normal cells, DNA methylation is involved in the regulation of gene expression, including chromatin organization and genomic imprinting. In contrast, global DNA hypomethylation in repetitive regions and hypermethylation in CpG islands of tumor suppressor gene promoters are observed in tumors, and increase in the activity of DNA methyltransferases. These alterations are also observed in HPV-induced carcinogenesis. HPV E7 binds to DNMT1 and stimulates its activity, and activates transcription of DNMT1 through the pRB/E2F pathway, while HPV E6 upregulates DNMT1 by suppression of p53. Increased expression of DNMT3A and 3B has also been observed in HPV-positive cells. Aberrant methylation occurs frequently in cervical cancer, leading to silencing of gene expression, activation of oncogenes and transposable elements, loss of imprinting, and inactivation of tumor suppressor genes.

• #21 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2

  In addition to genetic alterations, it has become evident that oncogenomic processes can be profoundly influenced by epigenetic mechanisms. Epigenetic alterations are often found early in tumorigenesis and are likely to be key initiating events in certain cancers. In addition to tumor initiation, epigenetic events also contribute to tumor progression. A number of epigenetic alterations have been identified that occur in both the HPV and the cellular genome, including DNA hypomethylation, hypermethylation of tumor suppressor genes, histone modifications, and alterations in ncRNAs. […] The earliest and most common molecular changes in the multistep carcinogenesis process is DNA methylation. In normal cells, DNA methylation is involved in the regulation of gene expression, including chromatin organization and genomic imprinting. In contrast, global DNA hypomethylation in repetitive regions and hypermethylation in CpG islands of tumor suppressor gene promoters are observed in tumors, and increase in the activity of DNA methyltransferases. These alterations are also observed in HPV-induced carcinogenesis. HPV E7 binds to DNMT1 and stimulates its activity, and activates transcription of DNMT1 through the pRB/E2F pathway, while HPV E6 upregulates DNMT1 by suppression of p53. Increased expression of DNMT3A and 3B has also been observed in HPV-positive cells. Aberrant methylation occurs frequently in cervical cancer, leading to silencing of gene expression, activation of oncogenes and transposable elements, loss of imprinting, and inactivation of tumor suppressor genes.

• #22 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2

  In addition to genetic alterations, it has become evident that oncogenomic processes can be profoundly influenced by epigenetic mechanisms. Epigenetic alterations are often found early in tumorigenesis and are likely to be key initiating events in certain cancers. In addition to tumor initiation, epigenetic events also contribute to tumor progression. A number of epigenetic alterations have been identified that occur in both the HPV and the cellular genome, including DNA hypomethylation, hypermethylation of tumor suppressor genes, histone modifications, and alterations in ncRNAs. […] The earliest and most common molecular changes in the multistep carcinogenesis process is DNA methylation. In normal cells, DNA methylation is involved in the regulation of gene expression, including chromatin organization and genomic imprinting. In contrast, global DNA hypomethylation in repetitive regions and hypermethylation in CpG islands of tumor suppressor gene promoters are observed in tumors, and increase in the activity of DNA methyltransferases. These alterations are also observed in HPV-induced carcinogenesis. HPV E7 binds to DNMT1 and stimulates its activity, and activates transcription of DNMT1 through the pRB/E2F pathway, while HPV E6 upregulates DNMT1 by suppression of p53. Increased expression of DNMT3A and 3B has also been observed in HPV-positive cells. Aberrant methylation occurs frequently in cervical cancer, leading to silencing of gene expression, activation of oncogenes and transposable elements, loss of imprinting, and inactivation of tumor suppressor genes.

• #23 RETRACTED ARTICLE: Molecular mechanisms in progression of HPV-associated cervical carcinogenesis | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0520-2

  The silencing of E6 and E7 was found to decrease methylation of tumour suppressor genes and reverse the transformed phenotype of cervical cancer cells. Methylation of HPV genes with concomitant silencing of HPV oncogenes could be a strategy of the virus to maintain a long-term infection by evading immune recognition. Several studies have shown that the frequency of DNA methylation of candidate genes increases with increasing severity of the cervical lesion, suggesting that these changes occur early in cancer development. […] Thus, the continuous activity of E6 and E7 proteins leads to aberrant cell proliferation, accumulation of oncogene mutations, and ultimately cervical cancer.

• #24 Cervical Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/253513-overview

  Human papillomavirus (HPV) infection must be present for cervical cancer to occur. […] HPV infection occurs in a high percentage of sexually active women. However, approximately 90% of HPV infections clear on their own within months to a few years and with no sequelae, although cytology reports in the 2 years following infection may show a low-grade squamous intraepithelial lesion. […] On average, only 5% of HPV infections will result in the development of CIN grade 2 or 3 lesions (the recognized cervical cancer precursor) within 3 years of infection. Only 20% of CIN 3 lesions progress to invasive cervical cancer within 5 years, and only 40% of CIN 3 lesions progress to invasive cervical cancer with 30 years. […] Because only a small proportion of HPV infections progress to cancer, other factors must be involved in the process of carcinogenesis. The following factors have been postulated to influence the development of CIN 3 lesions:

• #25 Cervical Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/253513-overview

  The type and duration of viral infection, with high-risk HPV type and persistent infection predicting a higher risk for progression; low-risk HPV types do not cause cervical cancer. […] Host conditions that compromise immunity (eg, poor nutritional status, immunocompromise, and HIV infection). […] Environmental factors (eg, smoking and vitamin deficiencies). […] Lack of access to routine cytology screening. […] Although use of oral contraceptives for 5 years or longer has been associated with an increased risk of cervical cancer, the increased risk may reflect a higher risk for HPV infection among sexually active women. However, a possible direct interaction between oral contraceptives and HPV infection has not been disproved. […] HPV comprises a heterogeneous group of viruses that contain closed circular double-stranded DNA. The viral genome encodes 6 early open reading frame proteins (ie, E1, E2, E3, E4, E6, and E7), which function as regulatory proteins, and 2 late open reading frame proteins (ie, L1 and L2), which make up the viral capsid.

• #26 Cervical Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/253513-overview

  The type and duration of viral infection, with high-risk HPV type and persistent infection predicting a higher risk for progression; low-risk HPV types do not cause cervical cancer. […] Host conditions that compromise immunity (eg, poor nutritional status, immunocompromise, and HIV infection). […] Environmental factors (eg, smoking and vitamin deficiencies). […] Lack of access to routine cytology screening. […] Although use of oral contraceptives for 5 years or longer has been associated with an increased risk of cervical cancer, the increased risk may reflect a higher risk for HPV infection among sexually active women. However, a possible direct interaction between oral contraceptives and HPV infection has not been disproved. […] HPV comprises a heterogeneous group of viruses that contain closed circular double-stranded DNA. The viral genome encodes 6 early open reading frame proteins (ie, E1, E2, E3, E4, E6, and E7), which function as regulatory proteins, and 2 late open reading frame proteins (ie, L1 and L2), which make up the viral capsid.

• #27 Cervical Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/253513-overview

  The type and duration of viral infection, with high-risk HPV type and persistent infection predicting a higher risk for progression; low-risk HPV types do not cause cervical cancer. […] Host conditions that compromise immunity (eg, poor nutritional status, immunocompromise, and HIV infection). […] Environmental factors (eg, smoking and vitamin deficiencies). […] Lack of access to routine cytology screening. […] Although use of oral contraceptives for 5 years or longer has been associated with an increased risk of cervical cancer, the increased risk may reflect a higher risk for HPV infection among sexually active women. However, a possible direct interaction between oral contraceptives and HPV infection has not been disproved. […] HPV comprises a heterogeneous group of viruses that contain closed circular double-stranded DNA. The viral genome encodes 6 early open reading frame proteins (ie, E1, E2, E3, E4, E6, and E7), which function as regulatory proteins, and 2 late open reading frame proteins (ie, L1 and L2), which make up the viral capsid.

• #28 Cervical Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/253513-overview

  The type and duration of viral infection, with high-risk HPV type and persistent infection predicting a higher risk for progression; low-risk HPV types do not cause cervical cancer. […] Host conditions that compromise immunity (eg, poor nutritional status, immunocompromise, and HIV infection). […] Environmental factors (eg, smoking and vitamin deficiencies). […] Lack of access to routine cytology screening. […] Although use of oral contraceptives for 5 years or longer has been associated with an increased risk of cervical cancer, the increased risk may reflect a higher risk for HPV infection among sexually active women. However, a possible direct interaction between oral contraceptives and HPV infection has not been disproved. […] HPV comprises a heterogeneous group of viruses that contain closed circular double-stranded DNA. The viral genome encodes 6 early open reading frame proteins (ie, E1, E2, E3, E4, E6, and E7), which function as regulatory proteins, and 2 late open reading frame proteins (ie, L1 and L2), which make up the viral capsid.

• #29 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis

  https://www.mdpi.com/2076-0817/12/12/1380

  Persistent HPV infection and a lower host immune response collectively support instigating carcinogenesis by conversion of a low-grade squamous intraepithelial lesion (LSIL) into a high-grade squamous intraepithelial lesion (HSIL), which ultimately transforms into an invasive form of cervical carcinoma. […] The involvement of HPV in cancer induction and progression can take many years for conversion into a carcinoma with the help of different tumor-stimulating steps, such as E6/E7 proteins that interact with cellular proteins. […] Additionally, a few reports have suggested that imbalanced immunity and chronic inflammation in the tumor microenvironment (TME) may provoke precancerous cervical lesions that turn into invasive cancer. […] The E6 protein is required for the maintenance of the episomal genome, and the E7 protein is responsible for the activation of the G1 to S-phase checkpoint and potentially controls transcriptional alterations in infected cells.

• #30 Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis

  https://www.mdpi.com/2076-0817/12/12/1380

  E7 activates the cell cycle in differentiating infected cells through interactions with pRb (retinoblastoma tumor suppressor protein) and other proteins p107 and p130 (called pocket proteins) via the sequence LXCXE in CR2 sequences. […] The E7 oncoprotein also controls DNA methylation by regulating cell propagation pathways; thus, epigenetic alterations occur via the Rb family of tumor-suppressor proteins. […] In HPV-infected cells, the E6 protein primarily represents the neoplastic effect abrogation of p53 depending on ubiquitin. […] The binding of E6 to p53 depends on E6-associated protein (E6AP). […] HPV can use the evasion process to escape the immune response. […] HPV uses a variety of immune evasion mechanisms to suppress immune responses and promote cancer progression. […] HPV can show an immune escape strategy not only by hiding itself from recognition by immune cells by downregulating viral antigens, but also by disturbing the expression of immune response proteins, which further encourages prolonged viral persistence. […] HPV can acquire all these strategies to evade an effective immune response, which may eventually support the prolonged persistence of HPV infection and cervical cancer progression.

• #31 4. Pathogenesis of cervical cancer – Eurocytology

  https://www.eurocytology.eu/course/cervical-cytology-2/4-pathogenesis-of-cervical-cancer/

  Cervical cancer epidemiology and aetiology of cervical carcinoma […] Mechanisms of HPV and other risk factors in oncogenesis […] It is widely accepted that invasive squamous cell carcinoma of the cervix, which is the commonest histological type, is preceded by a pre-invasive stage of the disease, where the abnormal cells are confined to the epithelium. This stage of non-invasive disease is known as cervical intraepithelial neoplasia (CIN) and is directly related to the processes of infection and integration of HPV as described in the previous chapter. […] The development of CIN involves a progression from early changes (CIN1) involving the deeper layers of the epithelium to full thickness involvement at its most severe (CIN3) equating to carcinoma in situ. […] CIN1 overlaps with HPV infection and usually resolves spontaneously within 9-12 months.

• #32 4. Pathogenesis of cervical cancer – Eurocytology

  https://www.eurocytology.eu/course/cervical-cytology-2/4-pathogenesis-of-cervical-cancer/

  Cervical cancer epidemiology and aetiology of cervical carcinoma […] Mechanisms of HPV and other risk factors in oncogenesis […] It is widely accepted that invasive squamous cell carcinoma of the cervix, which is the commonest histological type, is preceded by a pre-invasive stage of the disease, where the abnormal cells are confined to the epithelium. This stage of non-invasive disease is known as cervical intraepithelial neoplasia (CIN) and is directly related to the processes of infection and integration of HPV as described in the previous chapter. […] The development of CIN involves a progression from early changes (CIN1) involving the deeper layers of the epithelium to full thickness involvement at its most severe (CIN3) equating to carcinoma in situ. […] CIN1 overlaps with HPV infection and usually resolves spontaneously within 9-12 months.

• #33 4. Pathogenesis of cervical cancer – Eurocytology

  https://www.eurocytology.eu/course/cervical-cytology-2/4-pathogenesis-of-cervical-cancer/

  Cervical cancer epidemiology and aetiology of cervical carcinoma […] Mechanisms of HPV and other risk factors in oncogenesis […] It is widely accepted that invasive squamous cell carcinoma of the cervix, which is the commonest histological type, is preceded by a pre-invasive stage of the disease, where the abnormal cells are confined to the epithelium. This stage of non-invasive disease is known as cervical intraepithelial neoplasia (CIN) and is directly related to the processes of infection and integration of HPV as described in the previous chapter. […] The development of CIN involves a progression from early changes (CIN1) involving the deeper layers of the epithelium to full thickness involvement at its most severe (CIN3) equating to carcinoma in situ. […] CIN1 overlaps with HPV infection and usually resolves spontaneously within 9-12 months.

• #34 4. Pathogenesis of cervical cancer – Eurocytology

  https://www.eurocytology.eu/course/cervical-cytology-2/4-pathogenesis-of-cervical-cancer/

  Likelihood of progression depends on persistence of HPV, its integration into the host genome and its type. […] HPV16 and 33 have the highest risk of progression to CIN3 […] CIN2 and CIN3 are managed as high-grade CIN and usually treated by excision or ablation when diagnosed at colposcopy. […] CIN3 is defined by nuclear pleomorphism involving the full thickness of the squamous epithelium with mitotic activity at all levels. CIN3 (and severe dysplasia) equates to carcinoma in situ, which term is seldom used nowadays. […] Risk of progression is highest for CIN3 and inter-observer variation is considerably less than for CIN1 or CIN2.

• #35 4. Pathogenesis of cervical cancer – Eurocytology

  https://www.eurocytology.eu/course/cervical-cytology-2/4-pathogenesis-of-cervical-cancer/

  Likelihood of progression depends on persistence of HPV, its integration into the host genome and its type. […] HPV16 and 33 have the highest risk of progression to CIN3 […] CIN2 and CIN3 are managed as high-grade CIN and usually treated by excision or ablation when diagnosed at colposcopy. […] CIN3 is defined by nuclear pleomorphism involving the full thickness of the squamous epithelium with mitotic activity at all levels. CIN3 (and severe dysplasia) equates to carcinoma in situ, which term is seldom used nowadays. […] Risk of progression is highest for CIN3 and inter-observer variation is considerably less than for CIN1 or CIN2.

• #36 4. Pathogenesis of cervical cancer – Eurocytology

  https://www.eurocytology.eu/course/cervical-cytology-2/4-pathogenesis-of-cervical-cancer/

  Likelihood of progression depends on persistence of HPV, its integration into the host genome and its type. […] HPV16 and 33 have the highest risk of progression to CIN3 […] CIN2 and CIN3 are managed as high-grade CIN and usually treated by excision or ablation when diagnosed at colposcopy. […] CIN3 is defined by nuclear pleomorphism involving the full thickness of the squamous epithelium with mitotic activity at all levels. CIN3 (and severe dysplasia) equates to carcinoma in situ, which term is seldom used nowadays. […] Risk of progression is highest for CIN3 and inter-observer variation is considerably less than for CIN1 or CIN2.

• #37 4. Pathogenesis of cervical cancer – Eurocytology

  https://www.eurocytology.eu/course/cervical-cytology-2/4-pathogenesis-of-cervical-cancer/

  Likelihood of progression depends on persistence of HPV, its integration into the host genome and its type. […] HPV16 and 33 have the highest risk of progression to CIN3 […] CIN2 and CIN3 are managed as high-grade CIN and usually treated by excision or ablation when diagnosed at colposcopy. […] CIN3 is defined by nuclear pleomorphism involving the full thickness of the squamous epithelium with mitotic activity at all levels. CIN3 (and severe dysplasia) equates to carcinoma in situ, which term is seldom used nowadays. […] Risk of progression is highest for CIN3 and inter-observer variation is considerably less than for CIN1 or CIN2.

• #38 Untold story of human cervical cancers: HPV-negative cervical cancer

  https://www.bmbreports.org/journal/view.html?uid=1696&vmd=Full&

  Genetic mutations in cervical cancer can provide therapeutic targets. Most HPV-positive cervical cancers have either one or both mutations of PI3K-MAPK and TGFb signaling pathways. These genetic pathways are considered as therapeutic targets for HPV-positive cervical cancers. According to the TCGA study, HPV-negative cervical tumors were significantly associated with additional genomic mutations in KRAS, ARID1A, and PTEN compared to HPV-positive cervical tumors. This study highlights that unraveling mechanisms of PTEN and ARID1A mutations in HPV-negative cervical carcinoma can be a milestone to discover novel therapeutic targets. […] To overcome limited therapeutic options in HPV-negative cervical cancers, more fundamental research studies on the molecular etiology and identifying novel therapeutic targets of HPV-negative cervical cancer are needed. Current treatment guidelines do not demonstrate specialized treatment options based on the histological type of genomic signature of cervical carcinomas. Optimization of subtype-specific therapeutic strategies based on pathobiological features of cervical carcinoma can improve therapeutic outcomes. Novel therapeutic options may be suggested by discovering distinctive underlying molecular mechanisms of tumorigenesis in HPV-negative cervical carcinomas.

• #39 Untold story of human cervical cancers: HPV-negative cervical cancer

  https://www.bmbreports.org/journal/view.html?uid=1696&vmd=Full&

  Although the molecular etiology of HPV-negative cervical adenocarcinoma is unknown, several studies have suggested that mutations in TP53, PIK3CA, and CDKN2A are involved. HPV-negative cervical cancer shows the following clinical features. Cervical adenocarcinoma is frequently (15-38%) HPV-negative, although cervical squamous cell carcinoma is mostly HPV-positive. HPV-negative cervical cancer patients show significantly worse prognosis due to advanced International Federation of Gynecology and Obstetrics (FIGO) stage with lymphatic invasion at diagnosis than HPV-positive cervical cancer patients. […] HPV-negative cervical cancer may arise due to distinctive pathological pathway compared to HPV-positive cervical cancer. Nicols and colleagues showed higher prevalence of p53 mutation in HPV-negative cervical cancers than in HPV-positive ones, with 71% of HPV-negative cervical cancer cases displaying aberrant p53 immunostaining pattern with p16 overexpression. Since the strong link between p53 mutation and poor prognosis was shown by a previous research, the phenotypical characteristic might be the reason why HPV-negative cervical cancer showed more aggressive features including advanced FIGO stage, higher rate of metastasis, and poorer prognosis than HPV-positive one.

• #40 Untold story of human cervical cancers: HPV-negative cervical cancer

  https://www.bmbreports.org/journal/view.html?uid=1696&vmd=Full&

  Genetic mutations in cervical cancer can provide therapeutic targets. Most HPV-positive cervical cancers have either one or both mutations of PI3K-MAPK and TGFb signaling pathways. These genetic pathways are considered as therapeutic targets for HPV-positive cervical cancers. According to the TCGA study, HPV-negative cervical tumors were significantly associated with additional genomic mutations in KRAS, ARID1A, and PTEN compared to HPV-positive cervical tumors. This study highlights that unraveling mechanisms of PTEN and ARID1A mutations in HPV-negative cervical carcinoma can be a milestone to discover novel therapeutic targets. […] To overcome limited therapeutic options in HPV-negative cervical cancers, more fundamental research studies on the molecular etiology and identifying novel therapeutic targets of HPV-negative cervical cancer are needed. Current treatment guidelines do not demonstrate specialized treatment options based on the histological type of genomic signature of cervical carcinomas. Optimization of subtype-specific therapeutic strategies based on pathobiological features of cervical carcinoma can improve therapeutic outcomes. Novel therapeutic options may be suggested by discovering distinctive underlying molecular mechanisms of tumorigenesis in HPV-negative cervical carcinomas.

• #41 Molecular aspects of cervical cancer: a pathogenesis update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10985348/

  Cervical cancer (CC) is a significant health problem, especially in low-income countries. Functional studies on the human papillomavirus have generated essential advances in the knowledge of CC. However, many unanswered questions remain. This mini-review discusses the latest results on CC pathogenesis, HPV oncogenesis, and molecular changes identified through next-generation technologies. Interestingly, the percentage of samples with HPV genome integrations correlates with the degree of the cervical lesions, suggesting a role in the development of CC. Also, new functions have been described for the viral oncoproteins E5, E6, and E7, resulting in the acquisition and maintenance of cancer hallmarks, including proliferation, immune response evasion, apoptosis, and genomic instability. Remarkably, E5 oncoprotein affects signaling pathways involved in the expression of interferon-induced genes and EGFR-induced proliferation, while E6 and E7 oncoproteins regulate the DNA damage repair and cell cycle continuity pathways. Furthermore, next-generation technologies provide vast amounts of information, increasing our knowledge of changes in the genome, transcriptome, proteome, metabolome, and epigenome in CC. These studies have identified novel molecular traits associated with disease susceptibility, degree of progression, treatment response, and survival as potential biomarkers and therapeutic targets.

• #42 Expression signatures of HOX cluster genes in cervical cancer pathogenesis: Impact of human papillomavirus type 16 oncoprotein E7 | Oncotarget

  https://www.oncotarget.com/article/16619/text/

  The Homeobox (HOX) genes encode important transcription factors showing deregulated expression in several cancers. However, their role in cervical cancer pathogenesis, remains largely unexplored. Herein, we studied their association with Human Papillomavirus type 16 (HPV16) mediated cervical cancers. Our previously published gene expression microarray data revealed a significant alteration of 12 out of 39 HOX cluster members among cervical cancer cases, in comparison to the histopathologically normal controls. Of these, we validated seven (HOXA10, HOXA13, HOXB13, HOXC8, HOXC9, HOXC11 and HOXD10) by quantitative real-time PCR. We identified decreased HOXA10 expression as opposed to the increased expression of the rest. Such decrease was independent of the integration status of HPV16 genome, but correlated negatively with E7 expression in clinical samples, that was confirmed in vitro. HOXA10 and HOXB13 revealed association with Epithelial-Mesenchymal Transition (EMT). While HOXA10 expression correlated positively with E-Cadherin and negatively with Vimentin expression, HOXB13 showed the reverse trend. Chromatin immunoprecipitation study in vitro revealed the ability of E7 to increase HOX gene expression by epigenetic regulation, affecting the H3K4me3 and H3K27me3 status of their promoters, resulting from a loss of PRC2-LSD1 complex activity. Thus, besides identifying the deregulated expression of HOX cluster members in HPV16 positive cervical cancer and their association with EMT, our study highlighted the mechanism of HPV16 E7-mediated epigenetic regulation of HOX genes in such cancers, potentially serving as bedrock for functional studies in the future.

• #43 Expression signatures of HOX cluster genes in cervical cancer pathogenesis: Impact of human papillomavirus type 16 oncoprotein E7 | Oncotarget

  https://www.oncotarget.com/article/16619/text/

  The Homeobox (HOX) genes encode important transcription factors showing deregulated expression in several cancers. However, their role in cervical cancer pathogenesis, remains largely unexplored. Herein, we studied their association with Human Papillomavirus type 16 (HPV16) mediated cervical cancers. Our previously published gene expression microarray data revealed a significant alteration of 12 out of 39 HOX cluster members among cervical cancer cases, in comparison to the histopathologically normal controls. Of these, we validated seven (HOXA10, HOXA13, HOXB13, HOXC8, HOXC9, HOXC11 and HOXD10) by quantitative real-time PCR. We identified decreased HOXA10 expression as opposed to the increased expression of the rest. Such decrease was independent of the integration status of HPV16 genome, but correlated negatively with E7 expression in clinical samples, that was confirmed in vitro. HOXA10 and HOXB13 revealed association with Epithelial-Mesenchymal Transition (EMT). While HOXA10 expression correlated positively with E-Cadherin and negatively with Vimentin expression, HOXB13 showed the reverse trend. Chromatin immunoprecipitation study in vitro revealed the ability of E7 to increase HOX gene expression by epigenetic regulation, affecting the H3K4me3 and H3K27me3 status of their promoters, resulting from a loss of PRC2-LSD1 complex activity. Thus, besides identifying the deregulated expression of HOX cluster members in HPV16 positive cervical cancer and their association with EMT, our study highlighted the mechanism of HPV16 E7-mediated epigenetic regulation of HOX genes in such cancers, potentially serving as bedrock for functional studies in the future.

• #44 Expression signatures of HOX cluster genes in cervical cancer pathogenesis: Impact of human papillomavirus type 16 oncoprotein E7 | Oncotarget

  https://www.oncotarget.com/article/16619/text/

  The expression of genes belonging to the HOXC family, particularly HOXC4 to HOXC9, HOXC11, and HOXC13, shows predominant increase in most of the solid tumour types, except ovarian cancers. The two HOX genes most commonly activated in solid tumours are HOXA9 and HOXB13. Such activation of HOX cluster members are closely linked to the process of Epithelial-Mesenchymal Transition (EMT). […] The increased expression of majority of the HOX cluster members was also in line with our hypothesis of HPV16 E7 driven abrogation of PRC2-LSD1 complex activity leading to loss of gene silencing. A significant correlation of HOXA10 and HOXD10 expression with HPV16 E7 expression highlighted the impact of E7 on HOX gene expression. One of the possible mechanism of HOXA10 reduction could be through HPV16 E7-dependent activation of DNMT1 leading to HOXA10 promoter methylation. On the other hand, in our earlier report, we interpreted the increased HOXD10 expression in cervical cancer cases to be the result of E7-dependent inactivation of HOTAIR mediated gene silencing through PRC2-LSD1 complex. […] Thus taken together, through this study we establish the mechanism of E7-mediated activation of HOX gene expression through functional abrogation of HOTAIR, ultimately suppressing the PRC2-LSD1 complex activity, a model that we proposed in our previous study.

• #45 Expression signatures of HOX cluster genes in cervical cancer pathogenesis: Impact of human papillomavirus type 16 oncoprotein E7 | Oncotarget

  https://www.oncotarget.com/article/16619/text/

  The Homeobox (HOX) genes encode important transcription factors showing deregulated expression in several cancers. However, their role in cervical cancer pathogenesis, remains largely unexplored. Herein, we studied their association with Human Papillomavirus type 16 (HPV16) mediated cervical cancers. Our previously published gene expression microarray data revealed a significant alteration of 12 out of 39 HOX cluster members among cervical cancer cases, in comparison to the histopathologically normal controls. Of these, we validated seven (HOXA10, HOXA13, HOXB13, HOXC8, HOXC9, HOXC11 and HOXD10) by quantitative real-time PCR. We identified decreased HOXA10 expression as opposed to the increased expression of the rest. Such decrease was independent of the integration status of HPV16 genome, but correlated negatively with E7 expression in clinical samples, that was confirmed in vitro. HOXA10 and HOXB13 revealed association with Epithelial-Mesenchymal Transition (EMT). While HOXA10 expression correlated positively with E-Cadherin and negatively with Vimentin expression, HOXB13 showed the reverse trend. Chromatin immunoprecipitation study in vitro revealed the ability of E7 to increase HOX gene expression by epigenetic regulation, affecting the H3K4me3 and H3K27me3 status of their promoters, resulting from a loss of PRC2-LSD1 complex activity. Thus, besides identifying the deregulated expression of HOX cluster members in HPV16 positive cervical cancer and their association with EMT, our study highlighted the mechanism of HPV16 E7-mediated epigenetic regulation of HOX genes in such cancers, potentially serving as bedrock for functional studies in the future.

• #46 The promoting effect and mechanism of Nrf2 on cell metastasis in cervical cancer | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04287-0

  Cervical cancer (CC) has poor prognosis and high mortality rate for its metastasis during the disease progression. Epithelial-mesenchymal transition (EMT) and anoikis are initial and pivotal steps during the metastatic process. Although higher levels of Nrf2 are associated with aggressive tumor behaviors in cervical cancer, the detailed mechanism of Nrf2 in cervical cancer metastasis, especially EMT and anoikis, remains unclear. […] Nrf2 was highly expressed in patients with lymph node metastasis. And Nrf2 was proved to enhance the migration ability of HeLa and SiHa cells. In addition, Nrf2 was positively correlated with EMT processes and negatively associated with anoikis in cervical cancer. […] Our fundings established Nrf2 plays a crucial role in the metastasis of cervical cancer by enhancing EMT and resistance to anoikis by promoting the expression of Snail1, with potential value as a therapeutic candidate.

• #47 The promoting effect and mechanism of Nrf2 on cell metastasis in cervical cancer | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04287-0

  Cervical cancer (CC) has poor prognosis and high mortality rate for its metastasis during the disease progression. Epithelial-mesenchymal transition (EMT) and anoikis are initial and pivotal steps during the metastatic process. Although higher levels of Nrf2 are associated with aggressive tumor behaviors in cervical cancer, the detailed mechanism of Nrf2 in cervical cancer metastasis, especially EMT and anoikis, remains unclear. […] Nrf2 was highly expressed in patients with lymph node metastasis. And Nrf2 was proved to enhance the migration ability of HeLa and SiHa cells. In addition, Nrf2 was positively correlated with EMT processes and negatively associated with anoikis in cervical cancer. […] Our fundings established Nrf2 plays a crucial role in the metastasis of cervical cancer by enhancing EMT and resistance to anoikis by promoting the expression of Snail1, with potential value as a therapeutic candidate.

• #48 Bridging Links between Long Noncoding RNA HOTAIR and HPV Oncoprotein E7 in Cervical Cancer Pathogenesis | Scientific Reports

  https://www.nature.com/articles/srep11724

  Human Papillomavirus (HPV) type 16 oncoprotein E7 plays a major role in cervical carcinogenesis by interacting with and functionally inactivating various host regulatory molecules. […] Our study depicts one of the causal mechanisms of cervical carcinogenesis by HPV16 E7, through modulation of HOTAIR expression and function. […] HPV16 acts by frequently integrating into the host chromosome and replicates along with the host genome, which results in E2 gene disruption and consistent expression of the two HPV oncoproteins E6 and E7 due to loss of E2 repressor activity. […] It is well established that oncoproteins E6 and E7 are the major transforming agents, leading to carcinogenesis. […] Such global change at the transcriptional level is a common event associated with all cancers, including CaCx cases expressing HPV16 oncoprotein E7.

• #49 Bridging Links between Long Noncoding RNA HOTAIR and HPV Oncoprotein E7 in Cervical Cancer Pathogenesis | Scientific Reports

  https://www.nature.com/articles/srep11724

  Human Papillomavirus (HPV) type 16 oncoprotein E7 plays a major role in cervical carcinogenesis by interacting with and functionally inactivating various host regulatory molecules. […] Our study depicts one of the causal mechanisms of cervical carcinogenesis by HPV16 E7, through modulation of HOTAIR expression and function. […] HPV16 acts by frequently integrating into the host chromosome and replicates along with the host genome, which results in E2 gene disruption and consistent expression of the two HPV oncoproteins E6 and E7 due to loss of E2 repressor activity. […] It is well established that oncoproteins E6 and E7 are the major transforming agents, leading to carcinogenesis. […] Such global change at the transcriptional level is a common event associated with all cancers, including CaCx cases expressing HPV16 oncoprotein E7.

• #50 Bridging Links between Long Noncoding RNA HOTAIR and HPV Oncoprotein E7 in Cervical Cancer Pathogenesis | Scientific Reports

  https://www.nature.com/articles/srep11724

  Based on this rationale, we hypothesized that one of the mechanisms by which HPV16 E7 mediates its causal effect of activation of cancer-related pathway genes in CaCx pathogenesis, is through interplay with lncRNA HOTAIR. […] Our study revealed statistically significant down-regulation of HOTAIR expression in CaCx cases in comparison to the HPV negative controls. […] HOTAIR deregulation is likely to influence the expression of its downstream target genes through altered recruitment of PRC2-complex. […] HOTAIR down-regulation was concomitant with HOXD10 up-regulation among the CaCx cases, in our study. […] Our study is the first of its kind to depict that one of the causal mechanisms of cervical carcinogenesis mediated by HPV16 E7, was through modulation of HOTAIR expression and function.

• #51 Bridging Links between Long Noncoding RNA HOTAIR and HPV Oncoprotein E7 in Cervical Cancer Pathogenesis | Scientific Reports

  https://www.nature.com/articles/srep11724

  Based on this rationale, we hypothesized that one of the mechanisms by which HPV16 E7 mediates its causal effect of activation of cancer-related pathway genes in CaCx pathogenesis, is through interplay with lncRNA HOTAIR. […] Our study revealed statistically significant down-regulation of HOTAIR expression in CaCx cases in comparison to the HPV negative controls. […] HOTAIR deregulation is likely to influence the expression of its downstream target genes through altered recruitment of PRC2-complex. […] HOTAIR down-regulation was concomitant with HOXD10 up-regulation among the CaCx cases, in our study. […] Our study is the first of its kind to depict that one of the causal mechanisms of cervical carcinogenesis mediated by HPV16 E7, was through modulation of HOTAIR expression and function.

• #52 Potential mechanism of RRM2 for promoting Cervical Cancer based on weighted gene co-expression network analysis

  https://www.medsci.org/v17p2362.htm

  The Ribonucleotide reductase subunit M2 (RRM2) gene is located on chromosome 2p25, a region with no copy-number variations (CNVs) or other structural alterations in human cervical cancer samples. […] RRM2, as a component of ribonucleotide reductase (RNR), plays vital roles in many critical cellular processes such as cell proliferation, invasiveness, migration, angiogenesis and senescence. […] Upregulation of RRM2 was found to lead to promotion of angiogenesis, whereas its downregulation significantly increased apoptosis and promoted cell cycle arrest in cervical cancer. […] Our previous research has also shown that higher expression of RRM2 is associated with a significantly poorer overall survival. […] Therefore, for the main purpose of revealing the potential molecular mechanism of RRM2 for promoting the development of cervical cancer, we carried out our investigation based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO).

• #53 Potential mechanism of RRM2 for promoting Cervical Cancer based on weighted gene co-expression network analysis

  https://www.medsci.org/v17p2362.htm

  The Ribonucleotide reductase subunit M2 (RRM2) gene is located on chromosome 2p25, a region with no copy-number variations (CNVs) or other structural alterations in human cervical cancer samples. […] RRM2, as a component of ribonucleotide reductase (RNR), plays vital roles in many critical cellular processes such as cell proliferation, invasiveness, migration, angiogenesis and senescence. […] Upregulation of RRM2 was found to lead to promotion of angiogenesis, whereas its downregulation significantly increased apoptosis and promoted cell cycle arrest in cervical cancer. […] Our previous research has also shown that higher expression of RRM2 is associated with a significantly poorer overall survival. […] Therefore, for the main purpose of revealing the potential molecular mechanism of RRM2 for promoting the development of cervical cancer, we carried out our investigation based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO).

• #54 Potential mechanism of RRM2 for promoting Cervical Cancer based on weighted gene co-expression network analysis

  https://www.medsci.org/v17p2362.htm

  Interestingly, we found that RRM2 may exert its promoted role in cervical cancer by reducing the number of stromal cells, increasing the number of tumor cells and promoting lymphocyte infiltration. […] The results indicated that cervical cancer patients with high expression showed a significantly poorer OS (HR: 1.621; 95% CI: 0.03834-0.9929; P=0.044). […] The results of the present study found that RRM2 may exert its promoted effect in cervical cancer by reducing the number of stromal cells, increasing the number of tumor cells and promoting lymphocyte infiltration. […] RRM2 may co-express with RFC44 (correlated with stromal cells and tumor cells) to increase the number of tumor cells and reduce the number of stromal cells, and subsequently regulate the expression of the RPL family (RPL30, RPL23 and RPL3 et al.) or CENPI, KIF2A and CASCS (correlated with lymphocyte infiltration) to promote lymphocyte infiltration. […] In conclusion, the expression of RRM2 is upregulated in cervical cancer and promotes cancerous progression. RRM2 may exert its promoted role in cervical cancer by reducing the number of stromal cells, increasing the number of tumor cells and promoting lymphocyte infiltration.

• #55 Mechanism of hydrogen on cervical cancer suppression revealed by high‑throughput RNA sequencing

  https://www.spandidos-publications.com/10.3892/or.2021.8092

  Cervical cancer is considered one of the diseases with the highest mortality among women and with limited treatment options. Hydrogen (H2) inhalation has been reported to have a variety of tumor-suppressive effects, but the exact mechanism remains unclear. […] The results revealed an increased apoptosis rate, and reduced cell proliferation and oxidative stress in H2-treated HeLa cells but not in HaCaT cells. Similarly, decreased tumor growth and cell proliferation, and enhanced cell apoptosis were observed in H2-treated HeLa tumors. […] In conclusion, the present study reveals a novel mechanism of H2 against cervical cancer, which may serve as a potential therapeutic target in clinical practice. […] The present study first determined the pro-apoptotic and anti-proliferative effects of H2 treatment in HeLa cells. A H2 concentration of 33.3% significantly increased the cell apoptosis and reduced the cell proliferation of HeLa cells but not those of non-tumor HaCaT cells. Furthermore, a high concentration of H2 further inhibited HeLa cell proliferation and promoted cell apoptosis.

• #56 Mechanism of hydrogen on cervical cancer suppression revealed by high‑throughput RNA sequencing

  https://www.spandidos-publications.com/10.3892/or.2021.8092

  The present study demonstrated that both HIF1A (HIF-1 gene) and HIF-1 protein levels were reduced in H2-treated HeLa cells and HeLa tumors, which is important for elucidating the potential mechanisms of H2 gas on cervical cancer treatment. Notably, the reduced oxidative stress observed in HeLa cells may contradict the antitumor effects of H2. However, since ROS are essential in the stabilization of HIF that maintains the transcription of genes involved in tumor development, this downward trend of oxidative stress may be considered as an antitumor effect in general. […] In conclusion, the present study suggests a novel H2-induced tumor suppression target towards HIF-1 and NF-B. Inhibition of HIF-1 and NF-B reduces cervical cancer HeLa cell proliferation and oxidative stress level, and decreases tumor growth, which makes H2 therapy a potential target in the treatment of cervical cancer.

• #57

  https://profilesrns.times.uh.edu/profile/358185

  The objective of our research is to understand the mechanisms of progesterone receptor (PR) in suppressing cervical cancer. […] Although human papillomavirus (HPV) is required for the malignancy, it is not sufficient and other non-viral factors are implicated in cervical carcinogenesis. […] Our hypothesis is that PR is a ligand-dependent tumor suppressor in cervical cancer. […] These studies will provide further understanding of pathogenesis of cervical cancer and thereby facilitate the development of a new effective therapy for the disease.

• #58 Cervical Cancer: Oncogene YAP1 Plays Central Role in Carcinogenesis – Mass General Advances in Motion

  https://advances.massgeneral.org/obgyn/article.aspx?id=1392

  The exact etiology of cervical cancer is unknown, but contrary to previous understanding, new research finds that human papillomavirus (HPV) infection is not „a necessary step” for cervical carcinogenesis. […] New data show YAP1 oncogene hyperactivation alone can drive cervical carcinogenesis. […] When YAP1 hyperactivation combines with HPV infection, the synergy accelerates initiation and progression of cervical carcinogenesis. […] Data from Dr. Wang’s work suggest an evolving role for the YAP1 oncogene in cervical cancers, revealing an unconventional carcinogenesis mechanism. […] Dr. Wang notes that the skew between infection rate and disease prevalence indicates a role for individual genetic susceptibility. […] Hyperactivation of YAP1 in cervical epithelial cells facilitated HPV infection.

• #59 Cervical Cancer: Oncogene YAP1 Plays Central Role in Carcinogenesis – Mass General Advances in Motion

  https://advances.massgeneral.org/obgyn/article.aspx?id=1392

  The exact etiology of cervical cancer is unknown, but contrary to previous understanding, new research finds that human papillomavirus (HPV) infection is not „a necessary step” for cervical carcinogenesis. […] New data show YAP1 oncogene hyperactivation alone can drive cervical carcinogenesis. […] When YAP1 hyperactivation combines with HPV infection, the synergy accelerates initiation and progression of cervical carcinogenesis. […] Data from Dr. Wang’s work suggest an evolving role for the YAP1 oncogene in cervical cancers, revealing an unconventional carcinogenesis mechanism. […] Dr. Wang notes that the skew between infection rate and disease prevalence indicates a role for individual genetic susceptibility. […] Hyperactivation of YAP1 in cervical epithelial cells facilitated HPV infection.

• #60 Cervical Cancer: Oncogene YAP1 Plays Central Role in Carcinogenesis – Mass General Advances in Motion

  https://advances.massgeneral.org/obgyn/article.aspx?id=1392

  The exact etiology of cervical cancer is unknown, but contrary to previous understanding, new research finds that human papillomavirus (HPV) infection is not „a necessary step” for cervical carcinogenesis. […] New data show YAP1 oncogene hyperactivation alone can drive cervical carcinogenesis. […] When YAP1 hyperactivation combines with HPV infection, the synergy accelerates initiation and progression of cervical carcinogenesis. […] Data from Dr. Wang’s work suggest an evolving role for the YAP1 oncogene in cervical cancers, revealing an unconventional carcinogenesis mechanism. […] Dr. Wang notes that the skew between infection rate and disease prevalence indicates a role for individual genetic susceptibility. […] Hyperactivation of YAP1 in cervical epithelial cells facilitated HPV infection.

• #61 Cervical Cancer: Oncogene YAP1 Plays Central Role in Carcinogenesis – Mass General Advances in Motion

  https://advances.massgeneral.org/obgyn/article.aspx?id=1392

  The exact etiology of cervical cancer is unknown, but contrary to previous understanding, new research finds that human papillomavirus (HPV) infection is not „a necessary step” for cervical carcinogenesis. […] New data show YAP1 oncogene hyperactivation alone can drive cervical carcinogenesis. […] When YAP1 hyperactivation combines with HPV infection, the synergy accelerates initiation and progression of cervical carcinogenesis. […] Data from Dr. Wang’s work suggest an evolving role for the YAP1 oncogene in cervical cancers, revealing an unconventional carcinogenesis mechanism. […] Dr. Wang notes that the skew between infection rate and disease prevalence indicates a role for individual genetic susceptibility. […] Hyperactivation of YAP1 in cervical epithelial cells facilitated HPV infection.

• #62 Cervical Cancer: Oncogene YAP1 Plays Central Role in Carcinogenesis – Mass General Advances in Motion

  https://advances.massgeneral.org/obgyn/article.aspx?id=1392

  By synergizing with HPV, the YAP1 hyperactivation increases the putative HPV receptor molecules. […] The combined effects of HPV and YAP1 disrupt host cell innate immunity and weaken the defense against cancer of the cervix. […] These observations suggest that the disrupted Hippo/YAP signaling pathway likely plays a role in human cervical carcinogenesis and is associated with poor outcomes. […] Our study reveals an unconventional mechanism for cervical carcinogenesis. […] Dr. Wang’s laboratory is combining their unique animal models with high throughput technologies to uncover molecular mechanisms by which hyperactivated YAP1 alone or in combination with HPV drives cervical carcinogenesis. […] Researchers have provided in vitro and in vivo evidence that the YAP1 oncogene can induce cervical cancer regardless of HPV infection. Further, the synergism between HPV and YAP1 significantly accelerates the development of cervical cancer and HPV vaccination remains vitally important.

• #63 Cervical Cancer: Oncogene YAP1 Plays Central Role in Carcinogenesis – Mass General Advances in Motion

  https://advances.massgeneral.org/obgyn/article.aspx?id=1392

  By synergizing with HPV, the YAP1 hyperactivation increases the putative HPV receptor molecules. […] The combined effects of HPV and YAP1 disrupt host cell innate immunity and weaken the defense against cancer of the cervix. […] These observations suggest that the disrupted Hippo/YAP signaling pathway likely plays a role in human cervical carcinogenesis and is associated with poor outcomes. […] Our study reveals an unconventional mechanism for cervical carcinogenesis. […] Dr. Wang’s laboratory is combining their unique animal models with high throughput technologies to uncover molecular mechanisms by which hyperactivated YAP1 alone or in combination with HPV drives cervical carcinogenesis. […] Researchers have provided in vitro and in vivo evidence that the YAP1 oncogene can induce cervical cancer regardless of HPV infection. Further, the synergism between HPV and YAP1 significantly accelerates the development of cervical cancer and HPV vaccination remains vitally important.

• #64 Cervical Cancer: Oncogene YAP1 Plays Central Role in Carcinogenesis – Mass General Advances in Motion

  https://advances.massgeneral.org/obgyn/article.aspx?id=1392

  By synergizing with HPV, the YAP1 hyperactivation increases the putative HPV receptor molecules. […] The combined effects of HPV and YAP1 disrupt host cell innate immunity and weaken the defense against cancer of the cervix. […] These observations suggest that the disrupted Hippo/YAP signaling pathway likely plays a role in human cervical carcinogenesis and is associated with poor outcomes. […] Our study reveals an unconventional mechanism for cervical carcinogenesis. […] Dr. Wang’s laboratory is combining their unique animal models with high throughput technologies to uncover molecular mechanisms by which hyperactivated YAP1 alone or in combination with HPV drives cervical carcinogenesis. […] Researchers have provided in vitro and in vivo evidence that the YAP1 oncogene can induce cervical cancer regardless of HPV infection. Further, the synergism between HPV and YAP1 significantly accelerates the development of cervical cancer and HPV vaccination remains vitally important.

• #65 Key Molecular Events in Cervical Cancer Development

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6681523/

  Progression of HPV infected epithelial cells to invasive cancer is a long-term process associated with the accumulation of DNA alterations in host cell genes. These alterations involve both epigenetic and genetic changes in oncogenes and tumour suppressor genes. HPV enters the host basal squamous cells through a micro-wound or abrasion. The virus must be able to integrate into the host cell to initiate the infection, where a series of genetic events occur within the basal epithelial cells directly enabling viral replication. […] The HPV oncoproteins, mainly E6 and E7, play a major role in the alteration of host cellular function. HPVs overexpress E6 and E7 oncoproteins to disrupt the normal function of tumour suppressor genes in the host. Upon integration, the viral proteins begin to damage the host cells. Host cells have evolved a special mechanism to repair the damage inflicted upon their DNA via DNA damage response.

• #66 Key Molecular Events in Cervical Cancer Development

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6681523/

  The main reason for HPV to disrupt the host gene is so that it can continue to replicate and survive in the host tissue by exploiting the host cell cycle machinery. It is understood that the development of cervical cancer is a long process from normal to CIN 1, then CIN 2/3 and ultimately into cancer. […] The cells dysregulate several cellular functions to promote cell proliferation during the transition from precancerous to cancer. […] HPV infection plays a major role in cervical carcinogenesis. The overexpression of E6/E7 oncoproteins is the key factor that affects tumour suppressor genes, mainly those regulating the cell cycle, which then alters many downstream pathways leading to cancer progression. Understanding the key molecular mechanisms perturbed in the progression from HPV-infected cells to cervical intraepithelial neoplasia and finally to invasive cancer provides an insight into the multitude of pathways involved and inspires the future development of targeted therapies.

• #67 Key Molecular Events in Cervical Cancer Development

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6681523/

  The main reason for HPV to disrupt the host gene is so that it can continue to replicate and survive in the host tissue by exploiting the host cell cycle machinery. It is understood that the development of cervical cancer is a long process from normal to CIN 1, then CIN 2/3 and ultimately into cancer. […] The cells dysregulate several cellular functions to promote cell proliferation during the transition from precancerous to cancer. […] HPV infection plays a major role in cervical carcinogenesis. The overexpression of E6/E7 oncoproteins is the key factor that affects tumour suppressor genes, mainly those regulating the cell cycle, which then alters many downstream pathways leading to cancer progression. Understanding the key molecular mechanisms perturbed in the progression from HPV-infected cells to cervical intraepithelial neoplasia and finally to invasive cancer provides an insight into the multitude of pathways involved and inspires the future development of targeted therapies.

• #68 Key Molecular Events in Cervical Cancer Development

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6681523/

  The main reason for HPV to disrupt the host gene is so that it can continue to replicate and survive in the host tissue by exploiting the host cell cycle machinery. It is understood that the development of cervical cancer is a long process from normal to CIN 1, then CIN 2/3 and ultimately into cancer. […] The cells dysregulate several cellular functions to promote cell proliferation during the transition from precancerous to cancer. […] HPV infection plays a major role in cervical carcinogenesis. The overexpression of E6/E7 oncoproteins is the key factor that affects tumour suppressor genes, mainly those regulating the cell cycle, which then alters many downstream pathways leading to cancer progression. Understanding the key molecular mechanisms perturbed in the progression from HPV-infected cells to cervical intraepithelial neoplasia and finally to invasive cancer provides an insight into the multitude of pathways involved and inspires the future development of targeted therapies.

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