Materiały źródłowe

• #1 Nasopharyngeal Carcinoma (NPC, Lymphoepithelioma) – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK558922/

  Nasopharyngeal carcinoma (NPC), previously known as lymphoepithelioma, is a malignancy arising from the epithelium of the nasopharynx. […] A complex interplay of genetic susceptibility and Epstein Barr virus (EBV) infection is responsible for the disease. […] An interplay of environmental factors, genetic structure, and EBV infection is involved in the etiology of the disease. […] EBV is highly associated with NPC. Many studies illustrate multiple processes and mechanisms that EBV can activate or inhibit in the host cell while transforming it into a cancer cell. EBV affects the cells by bringing its encoded-proteins or RNA molecules that affect host cells, and these molecules could be summarized but not restricted to: […] Latent membrane protein 1 (LMP1): it is a membrane protein encoded by the virus, and plays a major role in inducing tumorigenesis. […] Many studies linked multiple genes to the pathogenesis of the NPC; one of these genes is a region in human leukocyte antigen (HLA) genes at chromosome 6. […] Other genes have been identified in different locations on different chromosomes such as 13q12, 3q26, 5p15, 6p21, and 9p21.

• #2 Nasopharyngeal carcinoma: A review of current updates

  https://www.spandidos-publications.com/10.3892/etm.2018.5878

  Nasopharyngeal carcinoma (NPC) is a rare malignancy worldwide, but it is endemic in a few areas including Southern China, Southeast Asia, North Africa and the Arctic. The underlying mechanisms behind this remarkable geographic distribution remain unclear. […] Although Epstein-Barr virus (EBV) infection has been suggested as a necessary cause of undifferentiated NPC, EBV itself is not sufficient to cause this malignancy. Other co-factors, such as environmental risk factors, and/or genetic susceptibility, may interact with EBV to play a role in the carcinogenesis of NPC. […] Evidence accumulated so far indicated a probable causal role of EBV in the pathogenesis of undifferentiated NPC (the most common histological subtype of NPC). […] Environmental exposures and/or genetic risk factors likely also play a role in the pathogenesis of this tumor.

• #2 Nasopharyngeal carcinoma: A review of current updates

  https://www.spandidos-publications.com/10.3892/etm.2018.5878

  The link between EBV and NPC was first proposed in 1966 when NPC patients were reported to have higher antibody response against an antigen that was later demonstrated as a product of EBV. […] Since then, extensive evidence suggests that EBV is a potential cause of NPC, especially type III. […] First, monoclonal EBV genome and viral gene products are detected in virtually all tumors in NPC-endemic areas, indicating that the tumors result from clonal proliferations of a single cell that is initially infected with EBV. […] Second, elevated IgA antibodies against EBV antigens are highly specific markers for subsequent NPC in high-incidence areas, while elevated EBV-neutralizing antibodies blocking B-cell infection and anti-gp350 antibodies are inversely associated with NPC risk. […] Third, the expression of viral proteins, such as latent membrane protein 1 (LMP1), LMP2, EBNA1 and EBNA2, has been demonstrated to drive tumor progression in invasive epithelial cancers.

• #3 The Pathogenesis and Therapeutics of Nasopharyngeal Carcinoma

  https://www.itmedicalteam.pl/articles/the-pathogenesis-and-therapeutics-of-nasopharyngeal-carcinoma-106094.html

  Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma and arises from nasopharynx epithelium, with a geographical and racial distribution. NPC has been demonstrated to be strongly associated with environmental factors, genetic susceptibility and viral infection, especially Epstein-Barr virus (EBV) infection. […] NPC initiation and progression is strongly associated with genetic susceptibility and viral infection, besides environmental factors. […] It has been documented that NPC development is strongly associated with three key etiological factors, including environmental factors such as chemical carcinogens and toxic pollutants, genetic susceptibility and viral infection, particularly, EBV infection. […] The previous studies have documented the strong association of genetic susceptibility with NPC occurrence.

• #3 The Pathogenesis and Therapeutics of Nasopharyngeal Carcinoma

  https://www.itmedicalteam.pl/articles/the-pathogenesis-and-therapeutics-of-nasopharyngeal-carcinoma-106094.html

  Viral infection, particularly Epstein-Barr virus (EBV) infection, has been demonstrated to be a critical etiological factor in NPC pathogenesis. EBV infection are particularly connected with the non-keratinizing types II and III NPC, which account for more than 95% of all NPC cases in Southern China, with the absence of EBV infection in type I NPC cases. […] High risky EBV variants characterized by distinct polymorphisms in the EBER locus are reported to have a strong association with NPC. […] EBV reactivation changed the balance between EBV and host body and induced NPC pathogenesis. […] NPC is prevalent in certain areas worldwide, with the involvement of multiple factors including genetic susceptibility, EBV infection and environmental exposure to chemical carcinogens. […] NPC is different from other head and neck carcinomas, with majority of NPC cases being in the limited endemic areas, particularly in Southern China, and being infected with EBV.

• #4 Carcinogenesis of nasopharyngeal carcinoma: an alternate hypothetical mechanism | Cancer Communications | Full Text

  https://cancercommun.biomedcentral.com/articles/10.1186/s40880-015-0068-9

  Current proposed mechanisms implicate both early and latent EpsteinBarr virus (EBV) infection in the carcinogenic cascade, whereas epidemiological studies have always associated nasopharyngeal carcinoma (NPC) with early childhood EBV infection and with chronic ear, nose, and sinus conditions. […] The EpsteinBarr virus (EBV) has been definitively implicated in the pathogenesis of NPC. […] We propose that there is a common genetic susceptibility in populations that are prone to NPC as a result of common ancestral origins, which in turn results in a tendency towards EBV chronic infection at an early age. Thereafter, the addition of some environmental insult (such as nitrosamines as previously proposed) results in the malignant transformation of the nasopharyngeal epithelium to NPC. […] Most NPC patients present with IgA antibodies to EBV viral capsid antigen (EBV-VCA) and EBV nuclear antigen 1 (EBNA1), and previous studies have shown that such IgA responses often precede tumor presentation by several years.

• #5 Pathogenesis and Etiology of Nasopharyngeal Carcinoma | SpringerLink

  https://link.springer.com/chapter/10.1007/174_2023_471

  Nasopharyngeal carcinoma (NPC) is an epithelial malignancy that originates from the nasopharynx, ubiquitously in the ostium of the Eustachian tube in the superior posterior wall of the nasopharynx. […] Despite sharing a tissue lineage with other mucosal head and neck cancers, NPC exhibits significant differences in its epidemiological distribution, pathogenic subtypes, etiologic factors, clinical features, and therapeutic approaches. […] It is characterized by the strong etiological and pathological association with Epstein-Barr virus (EBV) infection. […] Free-circulating plasma EBV DNA serves as a prognostic biomarker of pretreatment and posttreatment in EBV-related NPC in both endemic and non-endemic areas, and several researchers proposed to add the biomarker into the NPC TNM staging system.

• #6 Pathogenesis and Etiology of Nasopharyngeal Carcinoma | CoLab

  https://colab.ws/articles/10.1007%2F174_2023_471

  Nasopharyngeal carcinoma (NPC) is an epithelial malignancy that originates from the nasopharynx, ubiquitously in the ostium of the Eustachian tube in the superior posterior wall of the nasopharynx. […] NPC exhibits significant differences in its epidemiological distribution, pathogenic subtypes, etiologic factors, clinical features, and therapeutic approaches. […] It is characterized by the strong etiological and pathological association with Epstein-Barr virus (EBV) infection. Free-circulating plasma EBV DNA serves as a prognostic biomarker of pretreatment and posttreatment in EBV-related NPC in both endemic and non-endemic areas.

• #7 Pathogenesis of Nasopharyngeal Carcinoma | CoLab

  https://colab.ws/articles/10.1016%2FB978-0-12-814936-2.00003-1

  Nasopharyngeal carcinoma (NPC) arises from a unique anatomical site with heavy infiltration of leucocytes, predominantly T-lymphocytes, together with other stromal cells. […] EpsteinBarr virus (EBV) infection is closely associated with undifferentiated NPC. EBV infection in NPC is generally latent in nature. Expression of viral gene products may facilitate the malignant transformation of premalignant nasopharyngeal epithelium to NPC cells. […] Among the latent EBV gene products, the high expression of EBV-encoded BART-microRNAs in NPC is strongly implicated in NPC pathogenesis. A unique tumor microenvironment (TME) infiltrated heavily with T-lymphocytes and other stromal cells is believed to be involved to support growth of NPC in patients and latent EBV infection in NPC. […] Various cytokines secreted by EBV-infected NPC cells and the infiltrated stromal cells in the TME are involved in the recruitment of the rich cellular components to the tumor stroma. The dynamic and reciprocal interaction of cancer cells with stromal cells in the TME has been postulated to support EBV infection and modulate growth and invasive properties of NPC cells. […] Delineating the complex cancer cell-stromal cell interaction in NPC may reveal novel therapeutic targets effective for NPC treatment.

• #8 Interplay of Viral Infection, Host Cell Factors and Tumor Microenvironment in the Pathogenesis of Nasopharyngeal Carcinoma

  https://www.mdpi.com/2072-6694/10/4/106

  The roles of viral products expressed in the latency II program including LMP1/LMP2, EBNA1 and miR-BARTs in promoting NPC development and progression will be reviewed here. […] LMP1 has been well documented as a viral oncoprotein in EBV-associated malignancies. […] The oncogenic roles of LMP1 have been studied extensively and reviewed in details. […] Interestingly, expression of LMP1 is common in high-grade dysplastic lesions in the nasopharyngeal epithelium infected with EBV and has been implicated in facilitating the expansion of EBV-infected cell populations at early stage of NPC development. […] LMP1 could upregulate hexokinase 2 (HK2) via activation of c-Myc, upregulation of HK2 could also promote aerobic glycolysis and facilitate growth of tumor cells by blocking apoptosis under hypoxic conditions.

• #9 Interplay of Viral Infection, Host Cell Factors and Tumor Microenvironment in the Pathogenesis of Nasopharyngeal Carcinoma

  https://www.mdpi.com/2072-6694/10/4/106

  The fact that LMP1 contributes to the reprogramming of cancer metabolism further strengthens the role of EBV infection in adapting to alterations of host intracellular factors to promote NPC pathogenesis. […] Metastasis is common in NPC and is the major cause of treatment failure in patients. […] Multiple EBV-encoded viral products including LMP1, LMP2A and EBNA1 are involved in promoting NPC metastasis. […] LMP1 is able to promote NPC metastasis via different mechanisms. […] A recent study also demonstrated that through the suppression of miR-203 in an NF-κB-dependent manner, LMP1 can induce activation of cadherin 6 (CDH6) to act as the synergic node of multiple pathways to promote EMT. […] EBNA1 is also implicated in contributing to the metastatic process of NPC. […] The association of EBV infection with undifferentiated NPC has been well established.

• #10 The role of Exosomes in the Pathogenesis of Nasopharyngeal Carcinoma and the involved Clinical Application

  https://www.ijbs.com/v17p2147.htm

  The establishment of EBV latent infection in pre-invasive nasopharyngeal epithelium is considered to be an early stage of NPC pathogenesis. […] A mass of viral products are expressed during the latent phase of infection, including EB virus nuclear antigen (EBNA) 1, EB virus-encoded latent membrane proteins (LMP) 1 and 2, EB virus-encoded RNA (EBER), BamH A rightward transcripts (BART), and some incubation period mRNA, with which EBV-related exosomes coexist. […] LMP1 is predominantly produced in EBV infection, closely linked to the occurrence and growth of NPC. […] It has been shown to have multiple functions in vitro, covering promoting cell growth, protecting cells from apoptosis and enhancing cell motility. […] LMP1 packaged by exosomes can activate normal fibroblasts and turn them into cancer-related fibroblasts through the key signaling pathway of nuclear factor (NF)-B p65.

• #11 The role of Exosomes in the Pathogenesis of Nasopharyngeal Carcinoma and the involved Clinical Application

  https://www.ijbs.com/v17p2147.htm

  Studies have revealed that LMP1 in NPC exosomes upregulates syndecan-2 (SDC2) and synaptotagmin-like-4 (SYTL4) via NF-B signaling to stimulate the secretion of extracellular vesicles (EVs), promotes cell proliferation and tumor growth by activating ERK and AKT signal pathways and inducing vascular endothelial growth factor (VEGF) receptor expression. […] Exosomes can act as messengers to mediate cell communication and deliver the constituents to the recipient cells to perform crucial roles. […] The uptake of exosomes is not random, but dependent upon the interaction between the protein on the surface of the exosomes and the recipient cells. […] Exosomes can mediate continuous interference between cancer cells and stromal cells and the effect becomes stronger under hypoxic conditions.

• #12 Nasopharyngeal carcinoma: A new synthesis of literature data (Review)

  https://www.spandidos-publications.com/10.3892/etm.2021.11059

  Nasopharyngeal carcinoma (NPC) is an epithelial tumor, which develops most frequently from the lateral pharyngeal recess and holds some complex epidemiological characteristics. […] Causal factors for NPC development include: tobacco, alcohol and nitrosamine-containing food consumption. […] A first step in NPC development is considered to be the stable infection with EBV in the nasopharyngeal epithelium. […] The expression of lithic EBV genes has been detected along with the latent membrane protein 1 (LMP1) which can induce genomic instability and stimulate immune-suppressive cytokine release in order to evade immune recognition of the viral infected cells. […] One of the most studied oncoproteins is LMP1; it is considered to be the main EBV oncoprotein, which on the one hand can induce important genetic and epigenetic alterations, and on the other hand can promote cellular mobility, invasion and cervical lymph node metastasis, a unique characteristic of NPC.

• #13 Advances in targeted therapy mainly based on signal pathways for nasopharyngeal carcinoma | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-020-00340-2

  Nasopharyngeal carcinoma (NPC) is a malignant epithelial carcinoma of the head and neck region which mainly distributes in southern China and Southeast Asia and has a crucial association with the EpsteinBarr virus. […] The genetic and epigenetic alterations of NPC have been unveiled by the constant genome-wide studies, which involve cytogenic, allelotyping, CGH, and array-based CGH analysis. […] As an important cause of NPC, EBV infection leads to the expression of various latent viral proteins, such as latent membrane proteins (LMP1, LMP2), BamH1-A fragment rightward reading frame 1 (BARF1) and nuclear antigen (EBNA1). […] These viral and hosts genomic products affect the signal transductions and cellular mechanisms of normal nasopharyngeal epithelial cells and have major roles in the pathogenesis of NPC.

• #14 Advances in targeted therapy mainly based on signal pathways for nasopharyngeal carcinoma | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-020-00340-2

  The activation of the PI3K/Akt pathway is also related to EBV-encoded latent membrane proteins 1, 2A, 2B. […] The activation of the PI3K/Akt pathway is also related to EBV-encoded latent membrane proteins 1, 2A, 2B. […] In summary, in addition to directly targeted inhibition of PI3K, Akt, and mTOR, targeted inhibition of HIF-1, MK2, CCND1, lncRNA FAM225A, MYH9, MDK, miR-92a, miR-18a, EBV-miR-BART7-3p, FGF2, COL1A1, RBM3, PNUTS, Annexin A1, IL-8, CDKN3, c-Src, Flot-2, EpCAM, OCT4, BEX3, and targeted activation of LZTS2, UBQLN1, SMG1 may become potential therapeutic strategies that affecting the PI3K/Akt pathway in NPC.

• #15 Nasopharyngeal carcinoma: molecular pathogenesis and therapeutic developments | Expert Reviews in Molecular Medicine | Cambridge Core

  https://www.cambridge.org/core/journals/expert-reviews-in-molecular-medicine/article/nasopharyngeal-carcinoma-molecular-pathogenesis-and-therapeutic-developments/F84CD27189FE4E7FED9FD634EA557059

  Nasopharyngeal carcinoma (NPC) is a prevalent tumour in southern China and southeast Asia, particularly in the Cantonese population, where its incidence has remained high for decades. Recent studies have demonstrated that the aetiology of NPC is complex, involving multiple factors including genetic susceptibility, infection with the EpsteinBarr virus (EBV) and exposure to chemical carcinogens. During development of the disease, viral infection and multiple somatic genetic and epigenetic changes synergistically disrupt normal cell function, thus contributing to NPC pathogenesis. […] New biomarkers for NPC, including EBV DNA copy number or methylation of multiple tumour suppressor genes, which can be detected in serum and nasopharyngeal brushings, have been developed for the molecular diagnosis of this tumour. Meanwhile, new therapeutic strategies such as intensity-modulated radiation therapy and immuno- and epigenetic therapies might lead to more specific and effective treatments.

• #16 Genetic and epigenetic landscape of nasopharyngeal carcinoma – Dai – Chinese Clinical Oncology

  https://cco.amegroups.org/article/view/9478/html

  Nasopharyngeal carcinoma (NPC) is a unique epithelial malignancy that shows a remarkable geographical and ethic distribution. Multiple factors including predisposing genetic factors, environmental carcinogens, and Epstein-Barr virus (EBV) infection contribute to the accumulation of genetic and epigenetic alterations leading to NPC development. […] Genome-wide studies show that typically NPC tumors are characterized as having comparatively low mutation rates, widespread hypermethylation, and frequent copy number alterations and chromosome abnormalities. […] This model proposes a critical role of the genetic and epigenetic factors in the pathogenesis of NPC. […] Previous studies suggested that there are several cofactors that are associated with NPC development. They are the dietary factors, infection with an oncovirus, Epstein-Barr virus (EBV), and genetic predisposition. NPC is associated with genetic alterations on particular chromosomal regions and genes, harboring of specific cancer-associating single nucleotide polymorphisms (SNPs), and familial aggregation. Interestingly, recent studies confirm that epigenetic alterations, including the promoter hypermethylation, are also one of the crucial factors that are highly associated with NPC.

• #17 Molecular landscape and subtype-specific therapeutic response of nasopharyngeal carcinoma revealed by integrative pharmacogenomics | Nature Communications

  https://www.nature.com/articles/s41467-021-23379-3

  Through combinational chemoradiotherapy (CRT) screening, effective CRT regimens are also suggested for patients showing less sensitivity to radiation. […] Altogether, our study provides an example of applying integrative pharmacogenomics to establish a personalized precision oncology for NPC subtype-guided therapies. […] Earlier studies proposed an array of genetic factors and genetic aberrations leading to the development of NPC, including NF-B pathway activating mutations, chromatin modification-related mutations, ERBB-PI3K signaling activating mutations, etc. […] However, many questions, such as those regarding the major causative factors, the key driving pathways, druggable genetic targets in NPC, especially in different histological subtypes, are still unanswered clearly. […] The somatic mutation rate in NPC is relatively low compared to other types of cancers, with the somatic mutation rate of less than one per megabase, which is consistent with previous studies.

• #18 Molecular landscape and subtype-specific therapeutic response of nasopharyngeal carcinoma revealed by integrative pharmacogenomics | Nature Communications

  https://www.nature.com/articles/s41467-021-23379-3

  The recurred mutations presented revealed the oncogenic drivers of NPC, such as TP53, CYLD, KMT2C, NOTCH2, NFKBIA, FBXW7, ARID1A, PTEN, and BAP1. […] The mutation frequencies identified here were comparable with those reported by several previous studies, although they were, in general, lower than that of some other cancer types. […] Thus, as revealed by genomics analysis, some somatic CNVs and SNVs with distinct subtype-specific mutational frequencies were exhibited in different NPC subtypes, and they aggregated into several important signaling pathways, including microtubule polymerization, mitosis regulation, NF-B signaling, EMT/invasion, etc., which might contribute to the distinct histological and molecular features among NPC subtypes.

• #19 Nasopharyngeal Cancer and the Southeast Asian Patient | AAFP

  https://www.aafp.org/pubs/afp/issues/2001/0501/p1776.html

  Epstein-Barr virus, a herpesvirus, is the causative agent in acute infectious mononucleosis and is also associated with Hodgkin’s disease, Burkitt’s lymphoma, lymphoproliferative disease in the post-transplant setting, and T-cell lymphoma. The link between nasopharyngeal cancer and Epstein-Barr virus was first observed in 1966, when the sera of patients with the malignancy were found to manifest precipitating antibodies against cells infected with the virus. […] Genetic susceptibility has also been proposed as a risk factor for the development of nasopharyngeal cancer. Haplotypes that have been associated with the malignancy include certain human leukocyte antigens (HLA), including HLA-A2, HLA-B46 and HLA-B58.

• #20 Identifying Key Genes for Nasopharyngeal Carcinoma by Prioritized Consensus Differentially Expressed Genes Caused by Aberrant Methylation

  https://www.jcancer.org/v12p0874.htm

  Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated epithelial malignancy. […] NPC pathogenesis has been reported to be strongly associated with multiple factors, including host genetics, viral infection, and environmental effects, which can result in genetic and epigenetic alternations. […] Aberrant epigenetic alterations such as DNA methylation can disrupt or over-activate critical signaling pathways. Compared with other cancer types, such as liver, head and neck, colon, lung, thyroid, kidney, breast, pancreatic, and prostate cancers, NPC has a higher hypermethylation frequency. […] Genes downregulated by promoter hypermethylation could represent biomarkers for disease progression and prognosis in NPC. […] Through integrated analysis of DNA methylation and mRNA and miRNA expression profiles, we prioritized 56 hypermethylated downregulated genes, including 7 tumor suppressor genes, and constructed a miRNA-target regulation network consisting of 12 hypermethylated miRNAs and 25 upregulated oncogenes.

• #21 Genetic and epigenetic landscape of nasopharyngeal carcinoma – Dai – Chinese Clinical Oncology

  https://cco.amegroups.org/article/view/9478/html

  Aberrant epigenetic alterations, particularly DNA methylation, have been frequently reported in NPC. […] A number of tumor suppressors were found to be downregulated by promoter methylation. Aberrant methylation of tumor suppressors RASSF1 and CDKN2A was considered as important early events in NPC tumorigenesis. […] These results emphasize the importance of integrating the genetic and epigenetic changes to provide a comprehensive view of molecular changes in NPC. […] In NPC, EBV is harbored in a latent stage with restricted viral gene expression of LMP1/2, EBNA1, EBER1/2, and BARTs. LMP1 can activate cellular DNA methyltransferase via c-Jun NH2-terminal kinase signaling and upregulate BMI1 expression, which is associated with epigenetic changes in NPC. […] Although the high-throughput characterization methods, such as massive parallel sequencing, SNP, and methylation assays, has resulted in a greater understanding of NPC biology, yet much remains to be uncovered.

• #22 Identifying Key Genes for Nasopharyngeal Carcinoma by Prioritized Consensus Differentially Expressed Genes Caused by Aberrant Methylation

  https://www.jcancer.org/v12p0874.htm

  The promoter hypermethylation of PRKCB causing its downregulation was validated by experimental results and higher PRKCB expression was associated with longer overall survival in head-neck squamous cell carcinoma, suggesting the potential of PRKCB as a promising disease biomarker for NPC. […] Our integrative analysis provides reliable key genes for candidate biomarkers for diagnosis and prognosis in NPC. […] Hypermethylation in gene promoters is a well-known mechanism for the silencing of TSGs. […] We found 56 hypermethylated and downregulated genes in NPC. […] Among the 56 hypermethylated and downregulated genes, there were seven TSGs. […] Previous studies have reported that hypermethylation of HOPX, IRF8, and SHISA3 caused downregulation of gene expression and promoted the metastasis of NPC. […] Dysregulated transcription factor PRKCB could be an appropriate target for the development of anticancer drug.

• #23 Advances in targeted therapy mainly based on signal pathways for nasopharyngeal carcinoma | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-020-00340-2

  Mutations and repair disorders caused by viral infection are important causes of malignant changes in the nasopharyngeal epithelium. […] The epigenetic machinery of NPC cells could be altered to reprogram the epigenomes of virus and host cells through EBV-encoded proteins. […] The promoter hypermethylation of RASSF1A, BLU, CDKN2A, and DLEC1 could be detected in NPC, which have roles in DNA damage response, stress response, cell proliferation during G1 and STAT3 signal pathway. […] Targeted therapy involves the design of specific drugs that bind specifically to oncogenic targets within tumor cells to inhibit the development of tumors. […] In addition, abnormal activation and silencing of signal pathways in tumor cells also have a crucial role in tumor activities. […] Imbalance of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signal pathway is associated with malignant transformation and apoptosis of tumor cells, and metastasis and radioresistance of tumor tissues.

• #24 Interplay of Viral Infection, Host Cell Factors and Tumor Microenvironment in the Pathogenesis of Nasopharyngeal Carcinoma

  https://www.mdpi.com/2072-6694/10/4/106

  Undifferentiated nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV) infection. […] It has long been suggested that substantial and interactive impacts between cancer and stromal cells create a tumor microenvironment (TME) to promote tumorigenesis. […] The coexistence of tumor-infiltrating lymphocytes with EBV-infected NPC cells represents a distinct TME which supports immune evasion and cancer development from the early phase of EBV infection. […] Intracellularly, EBV-encoded viral products alter host cell signaling to facilitate tumor development and progression. […] Intercellularly, EBV-infected cancer cells communicate with stromal cells through secretion of cytokines and chemokines, or via release of tumor exosomes, to repress immune surveillance and enhance metastasis.

• #25 Interplay of Viral Infection, Host Cell Factors and Tumor Microenvironment in the Pathogenesis of Nasopharyngeal Carcinoma

  https://www.mdpi.com/2072-6694/10/4/106

  Although high expression of miR-BARTs has been detected in NPC patients, contributions of these more recently discovered viral products to the establishment of TME are still vaguely defined. […] The oncogenic property of EBV is supported by its ability to immortalize and transform primary B-cells in vitro. […] However, EBV episomes are readily detected and maintained at high levels in NPC patients. […] There is growing evidence to support that EBV-infected NPC cells can secrete cytokines and exosomes containing viral products to modulate the function of stromal cells in TME to facilitate NPC progression and evade host immune attacks. […] The modulation of host cell signaling plays important roles in suppressing senescence and apoptosis, promoting cell growth and facilitating malignant transformation of infected cells.

• #26 The role of Exosomes in the Pathogenesis of Nasopharyngeal Carcinoma and the involved Clinical Application

  https://www.ijbs.com/v17p2147.htm

  Exosome-derived cytokines and substances, such as galectin-9 and CCL20, can induce local accumulation of regulatory T cells (Tregs) and promote NPC aggressiveness. […] The immunomodulatory protein galactin-9 in EBV-infected NPC exosomes binds to ligand Tim-3, triggering apoptosis of mature CD4+ lymphocytes. […] Exosomes can arouse radioresistance by enhancing intercellular communication and cytotoxic damage in NPC cells. […] In general, exosomes play a prominent role in transmitting radioresistance in NPC. […] NPC patients also develop resistance to drugs, where exosomes may be the transmitter. […] Exosomes can provide protection for their contents against proteolytic digestion or drug action, which may be one of the causes for the failure of drug effect on NPC treatment, as exosomal cancer-promoting molecules move from the cancerous cells to the recipient cells.

• #27

  https://journals.lww.com/md-journal/fulltext/2023/12010/anti_nasopharyngeal_carcinoma_mechanism_of.41.aspx

  The MAPK signaling pathway is involved in the occurrence and development of NPC. […] The effect of SAN on the MAPK/ERK signaling pathway was verified and revealed that SAN can inhibit the expression level of the key proteins in the signaling pathway, including p-c-Raf, p-MEK, and ERK1/2, which was consistent with previous studies, indicating that SAN can inhibit proliferation and induce apoptosis of NPC cells via the MAPK/ERK signaling pathway. […] SAN can inhibit the proliferation and induce the apoptosis of NPC cells via the MAPK/ERK signaling pathway. The core targets of this mechanism action include EGFR, TP53, F2, FN1, PLAU, MMP9, SERPINE1, and CDK1.

• #28 Feature Reviews of the Molecular Mechanisms of Nasopharyngeal Carcinoma

  https://www.mdpi.com/2227-9059/11/6/1528

  EBV gene products often provide a cell proliferation advantage and anti-death signal. Therefore, targeting the EBV genome or the signaling pathways it stimulates is an attractive way to treat EBV-positive cancers. […] The activation of the PI3K/Akt pathway by EBV is thought to contribute to the development of NPC. […] Dysregulation of TGF-β/SMAD signaling pathways have been found to be frequent in NPC. […] The Wnt/β-catenin pathway is involved in the development and progression of some solid and hematologic malignancies. […] Epigenetic dysregulation is a hallmark of NPC tumorigenesis. Host genetics, EBV infection, and environmental factors contribute to epigenetic changes, ultimately leading to NPC development.

• #29 Current approach and novel perspectives in nasopharyngeal carcinoma: the role of targeting proteasome dysregulation as a molecular landmark in nasopharyngeal cancer | Journal of Experimental & Clinical Cancer Research | Full Text

  https://jeccr.biomedcentral.com/articles/10.1186/s13046-021-02010-9

  LMP1 is a transmembrane protein which belongs to the tumor necrosis factor receptor (TNFR) family and is constitutively activated in EBV infected cells leading to further activation of multiple downstream signaling pathways in a ligand-independent manner. […] Different studies suggest that LMP1 protein is rapidly degraded via proteasome-mediated proteolysis in physiologic conditions. […] In this sense, overexpression of Id1 (inhibitor of DNA binding/differentiation 1) seems to further stabilize LPM1 protein in EBV-infected cells. […] As a consequence, proteasome inhibitors may effectively stabilize this protein in EBV-positive NPCs. […] Overexpression of the protooncogene MDM2 has also been widely reported in NPC samples, and its presence has been associated to both EBV infection as well as to tumor metastasis.

• #30 Carcinogenesis of nasopharyngeal carcinoma: an alternate hypothetical mechanism | Cancer Communications | Full Text

  https://cancercommun.biomedcentral.com/articles/10.1186/s40880-015-0068-9

  We postulate that NPC carcinogenesis follows a similar model. Neonatal transmission of EBV infects the nasopharyngeal epithelium with resultant latency in the basal epithelium (salivary gland cells) during the developmental period of the transformational zone. Entry of the virus into the epithelial cells may perhaps be mediated in this case by integrin 6. Exposure to subsequent carcinogenic insults triggers the carcinogenic cascade that takes years for the eventual malignant transformation to NPC.

• #31 Nasopharyngeal carcinoma: A review of current updates

  https://www.spandidos-publications.com/10.3892/etm.2018.5878

  The household environment during childhood, when primary EBV infection is most probable, including number of siblings and population density of the household, could be important predictors for the immunological control of EBV and eventual EBV-related disease risk. […] Hence, we hypothesized that very early exposure to EBV and other carcinogens may play a role in NPC pathogenesis.

• #32 The role of Exosomes in the Pathogenesis of Nasopharyngeal Carcinoma and the involved Clinical Application

  https://www.ijbs.com/v17p2147.htm

  Exosomes are nanoscale membrane vesicles, which carry biologically active substances of their cell of origin and play an important role in signal transduction and intercellular communication. […] At present, exosomes have been identified as a promising non-invasive liquid biopsy biomarker in the tissues and circulating blood of nasopharyngeal carcinoma (NPC) and found to participate in regulating pathophysiological process of the tumor. […] We here review recent insights gained into the molecular mechanisms of exosome-induced cell growth, angiogenesis, metastasis, immunosuppression, radiation resistance and chemotherapy resistance in the development and progression of NPC, as well as the clinical application of exosomes as diagnostic biomarkers and therapeutic agents. […] The poor prognosis of NPC is mainly attributed to insufficient consciousness of the prominent symptoms of the disease, the limited detections and therapeutic options.

• #33 The role of Exosomes in the Pathogenesis of Nasopharyngeal Carcinoma and the involved Clinical Application

  https://www.ijbs.com/v17p2147.htm

  In order to improve the prognosis of the patients, it is necessary to better understand the pathogenesis of NPC and to develop new therapeutic targets and effective strategies. […] Exosomes are of great significance in the occurrence and progression of NPC, which can be classified into EBV-related exosomes, exosomes derived from NPC cells or mesenchymal stem cells, and other types of exosomes. […] There is growing evidence that different types of exosomes target their respective receptors to exert a variety of biological effects on NPC cell proliferation and function, resulting in promoting or suppressing the tumor growth. […] Exosomes related to NPC have definite significance for the occurrence and progression of NPC. […] The onset of NPC is etiologically associated with EBV infection.

• #34 Metastasis of nasopharyngeal carcinoma: What we know and do not know | Visualized Cancer Medicine

  https://vcm.edpsciences.org/articles/vcm/full_html/2021/01/vcm20200018/vcm20200018.html

  Nasopharyngeal carcinoma (NPC) has the highest metastatic rate among head and neck cancers, with its underlying mechanism not yet fully unveiled. […] Epstein-Barr virus (EBV) infection can trigger NPC metastasis from multiple angles via multiple signaling pathways. […] The molecules that promote and inhibit NPC metastasis are introduced, with a focus on cytokines SPINK6, serglycin, interleukin 8 (IL8), Wnt family member 5A (WNT5A), and chemokine C-C motif ligand 2 (CCL2). […] The transition of epithelial cells to mesenchymal like-cells is called epithelial-to-mesenchymal transition (EMT). It is widely believed that EMT is the initial step in the cascade of cancer metastasis. […] Based on our findings and other reports, the metastatic ability of NPC cells correlates with EMT. […] EBV is a latent infection in more than 90% of adults worldwide. It is associated with NPC and lymphoid malignancies, such as Burkitts lymphoma.

• #35

  https://www.grc.org/nasopharyngeal-carcinoma-conference/2016/

  „Detection and Screening for NPC with Trans-Oral Brushing and Determination of EBV DNA” […] „Development of Small Molecule Inhibitors of EBNA1 for the Treatment of Nasopharyngeal Carcinoma” […] „EBV-Encoded LMP1 Induces a Myofibroblast-Like Phenotype in Epithelial Cells via Epithelial-to-Mesenchymal Transition” […] „Future Focus for Basic NPC and EBV Studies”.

• #36 The role of Exosomes in the Pathogenesis of Nasopharyngeal Carcinoma and the involved Clinical Application

  https://www.ijbs.com/v17p2147.htm

  The level of endogenous HIF1 can be enhanced by LMP1 while exosomal HIF1 is supportive for the pro-invasive potential of LMP1-positive exosomes associated with NPC. […] The level of LMP1 is positively correlated with the expression of EMT markers and it functions to activate MMPs and miR-10b, inhibit miR-204, and consequently benefits the invasion and metastasis of NPC. […] The salient feature of NPC is the infiltration of a large number of non-malignant white blood cells in the primary tumor, mainly consisting of T lymphocytes and a small number of B cells, macrophages and dendritic cells, etc. […] However, this leukocyte infiltration has been found to disappear in the process of metastasis, replaced by rapidly and massively proliferated malignant cells with obvious anti-tumor immune feature.

• #37 MiRNAs in Radiotherapy Resistance of Nasopharyngeal Carcinoma

  https://www.jcancer.org/v11p3976.htm

  Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors of the head and neck in Southeast Asia and southern China. […] Radiotherapy resistance is the main cause of poor prognosis in NPC patients. […] The abnormal expression of miRNAs is closely related to radiotherapy sensitivity and prognosis of NPC patients, which can affect the transmission of related signaling pathways by regulating the expression of tumor suppressor genes and / or oncogenes, and therefore participate in radiotherapy resistance in nasopharyngeal carcinoma. […] Radiotherapy resistance is the leading cause of local recurrence and distant metastasis. […] Many studies have shown that miRNAs participate in tumor radiation resistance through the above mechanisms. […] Abnormal expression of apoptosis-related genes can inhibit the apoptosis of tumor cells induced by ionizing radiation and increase their survival, thereby promoting the radiotherapy resistance of NPC.

• #38 MiRNAs in Radiotherapy Resistance of Nasopharyngeal Carcinoma

  https://www.jcancer.org/v11p3976.htm

  The abnormal activation and expression of cell proliferation genes is also one of the mechanisms of tumor radiotherapy resistance. […] Studies have shown that up-regulation of Bcl-2 expression can inhibit the expression of Bax, caspase-3 and other apoptotic genes and promotes the survival of nasopharyngeal carcinoma cells, thus playing a role in the development and metastasis of nasopharyngeal carcinoma. […] Radiation directly ionizes target cell DNA or ionize water to generate free radicals that cause DNA damage in target cells, including double strained break (DSB) and single strained break (SSB). […] The hallmark of DNA double-strand break (DSB) is phosphorylation of histone H2AX in chromatin to produce -H2AX. […] The repair of DNA damage greatly affects the survival of tumor cells, producing the resistance of radiotherapy.

• #39 MiRNAs in Radiotherapy Resistance of Nasopharyngeal Carcinoma

  https://www.jcancer.org/v11p3976.htm

  The most sensitive to radiation in the cell cycle is the M phase, followed by the G2 phase, and the cells in the G1 and S phases are less sensitive to radiation. […] Since miRNA was discovered in Caenorhabditis elegans, its role as a non-coding RNA in regulating various biological behaviors of animals and plants has received widespread attention, especially in oncology. […] Many miRNAs have been found to be differentially expressed between patients with nasopharyngeal carcinoma and normal people. […] These up-regulated or down-regulated miRNAs can regulate the radiotherapy resistance of nasopharyngeal carcinoma cells by acting on different target genes and pathways. […] For example, miR-205 inhibits PTEN, thereby promoting AKT to increase the resistance of nasopharyngeal carcinoma cells to radiation, facilitating their survival after irradiation.

• #40 MiRNAs in Radiotherapy Resistance of Nasopharyngeal Carcinoma

  https://www.jcancer.org/v11p3976.htm

  MiR-20a-5p reduces the sensitivity of nasopharyngeal carcinoma cells to radiotherapy by targeting NPAS2 and Rab27B, and miR-193a-3p enhances the anti-radiation ability of NPC by targeting SRSF2. […] MiR-19b-3p, miR-125b, miR-21, and miR-205 promote the radiotherapy resistance of nasopharyngeal carcinoma by regulating the Bcl-2 gene family protein. […] The researchers found that up-regulated miR-21 and miR-BART4 or down-regulated miR-143 and miR-153 in nasopharyngeal carcinoma can inhibit the apoptosis of nasopharyngeal carcinoma cells via Fas or Caspase pathway, accompanied by or not with the regulation of Bcl-2 family proteins, and the sensitivity of nasopharyngeal carcinoma cells to radiotherapy is reduced. […] EBV-encoded miR-BART4 promotes proliferation and invasion of nasopharyngeal carcinoma cells in nasopharyngeal carcinoma, and promotes radioresistance of nasopharyngeal carcinoma.

• #41 Current Immune-Related Molecular Approach in Combating Nasopharyngeal Cancer | Gondhowiardjo | World Journal of Oncology

  https://www.wjon.org/index.php/wjon/article/view/1214/935

  In normal condition, cells infected by virus will present the viral antigen through major histocompatibility complex (MHC) Class I complex thereby attracting cytotoxic T cells to eliminate the infection. However, in EBV infection in epithelial pharyngeal cells, there are multiple EBV proteins, such as BCRF1, BILF and BNLF2a, which work to inhibit antigen presentation processes. […] Complicating the situation, cancer cells are able to downplay pro-inflammatory signals. There is evidence indicating local tumor microenvironment milieu bathed with immune suppression signals in nasopharyngeal cancer. […] Based on the understanding of EBV-associated nasopharyngeal cancer pathogenesis and mechanism of immune escape, several novel approaches can be employed to combat nasopharyngeal cancer. Targeting pathways that lead to cancer progression such as targeting EBV proteins or blocking downstream pathway that promotes survival may be an option, but this approach seems to only retard cancer cells progression and does not specifically result in cancer cell death.

• #42 Current approach and novel perspectives in nasopharyngeal carcinoma: the role of targeting proteasome dysregulation as a molecular landmark in nasopharyngeal cancer | Journal of Experimental & Clinical Cancer Research | Full Text

  https://jeccr.biomedcentral.com/articles/10.1186/s13046-021-02010-9

  Nasopharyngeal carcinoma (NPC) represents a molecularly paradigmatic tumor given the complex diversity of environmental as well as host dependent factors that are closely implicated in tissue transformation and carcinogenesis. Epstein Barr Virus (EBV) plays a key role in tissue invasion, hyperplasia and malignant transformation. Therefore, EBV related oncoviral proteins such as Latent Membrane Protein family (LMP1, LMP2), Epstein Barr Nuclear Antigen 1 (EBNA1) and EBV related glycoprotein B (gB) are responsible for inducing intracellular signalling aberrations leading to sustained proliferation and further acquisition of NPC related invasive nature and metastatic potential. […] Dysregulation of proteasome signaling seems to be centrally implicated in oncoviral protein stabilization as well as in modulating tumor microenvironment. Different studies in vitro and in vivo suggest a potential role of proteasome inhibitors in the therapeutic setting of NPC. Furthermore, alterations affecting proteasome signalling in NPC have been associated to tumor growth and invasion, distant metastasis, immune exclusion and resistance as well as to clinical poor prognosis.

• #43 Current approach and novel perspectives in nasopharyngeal carcinoma: the role of targeting proteasome dysregulation as a molecular landmark in nasopharyngeal cancer | Journal of Experimental & Clinical Cancer Research | Full Text

  https://jeccr.biomedcentral.com/articles/10.1186/s13046-021-02010-9

  In this work, our goal is to thoroughly review the molecular implications of proteasome dysregulation in the molecular pathogenesis of NPC, together with their direct relationship with EBV related oncoviral proteins and their role in promoting immune evasion and resistance. […] Proteasomes are responsible for the degradation of ubiquitinated proteins, and its role has been extensively documented in EBV-positive NPCs. Ubiquitin system is responsible for protein processing and degradation. In this sense, targeted proteins are primarily poly-ubiquitinated and eventually degraded by the 26S subunit. […] Cancer cells are highly dependent on proteasome-mediated degradation because of their intrinsically accelerated tumor turn-over. Thus, therapeutic efforts have been directed so as to promote direct proteasome inhibition which may in turn facilitate intracellular protein accumulation. An excess of intracellular misfolded protein-burden leads to further endoplasmic reticulum stress and cellular death. EBV induced proteasome truncation seems to be centrally implicated in viral replication as well as in EBV-induced carcinogenesis.

• #44 Current approach and novel perspectives in nasopharyngeal carcinoma: the role of targeting proteasome dysregulation as a molecular landmark in nasopharyngeal cancer | Journal of Experimental & Clinical Cancer Research | Full Text

  https://jeccr.biomedcentral.com/articles/10.1186/s13046-021-02010-9

  LMP1 is a transmembrane protein which belongs to the tumor necrosis factor receptor (TNFR) family and is constitutively activated in EBV infected cells leading to further activation of multiple downstream signaling pathways in a ligand-independent manner. […] Different studies suggest that LMP1 protein is rapidly degraded via proteasome-mediated proteolysis in physiologic conditions. […] In this sense, overexpression of Id1 (inhibitor of DNA binding/differentiation 1) seems to further stabilize LPM1 protein in EBV-infected cells. […] As a consequence, proteasome inhibitors may effectively stabilize this protein in EBV-positive NPCs. […] Overexpression of the protooncogene MDM2 has also been widely reported in NPC samples, and its presence has been associated to both EBV infection as well as to tumor metastasis.

• #45 Meta-Analysis illustrates possible role of lipopolysaccharide (LPS)-induced tissue injury in nasopharyngeal carcinoma (NPC) pathogenesis | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0258187

  Meta-Analysis illustrates possible role of lipopolysaccharide (LPS)-induced tissue injury in nasopharyngeal carcinoma (NPC) pathogenesis […] Nasopharyngeal carcinoma (NPC) is a cancer of epithelial origin with a high incidence in certain populations. […] Our meta-analysis identified activation of lipopolysaccharide (LPS)-induced tissue injury in NPC tissue. Additionally, interleukin-1 (IL-1) and SB203580 were the top upstream regulators. […] Our analysis illustrates that nasal epithelial barrier dysregulation and maladaptive immune responses are key components of NPC pathogenesis along with LPS-induced tissue damage. […] Further studies are required to better understand molecular mechanisms involved in NPC pathophysiology, such as the roles of lipopolysaccharide (LPS) and general inflammation on nasopharyngeal tissue injury, HOXA10 and matrix metalloproteinases 1 and 3 (MMP1, MMP3) pathways. […] LPS is a bacterial endotoxin on gram negative bacteria and makes contact with the nasopharynx through normal airflow and eating that can lead to the induction of numerous pathological pathways associated with immune defense. […] Specifically, LPS stimulates multiple inflammatory pathways through toll-like receptor 4 (TLR4), leading to expression of prostaglandin E2 along with tumor necrosis factor (TNF) and IL-1B, as shown in our analysis. […] Importantly, through IPA we found a link between LPS and IL-1B activation.

• #46 Mechanism of luteolin induces ferroptosis in nasopharyngeal carcinoma cells

  https://www.jstage.jst.go.jp/article/jts/49/9/49_399/_html/-char/en

  Nasopharyngeal carcinoma (NPC) originates from the nasopharynx epithelium, and luteolin is recognized as an important anti-cancer agent. This study investigated the effects of luteolin on ferroptosis in NPC cells. Luteolin treatment induced cell ferroptosis, evidenced by decreased cell viability, increased MDA and Fe2+ levels, and reduced SOD, GSH, and GPX4 levels. Furthermore, luteolin downregulated SOX4 expression, while overexpression of SOX4 reversed luteolin’s pro-ferroptotic effects in NPC cells. SOX4 was found to up-regulate GDF15 transcription by directly binding to its promoter. Conversely, overexpression of GDF15 mitigated the ferroptotic effects induced by luteolin in NPC cells. Therefore, luteolin induces ferroptosis in NPC cells via modulation of the SOX4/GDF15 axis. In conclusion, luteolin reduces the binding of SOX4 to the GDF15 promoter by suppressing SOX4 expression, thereby down-regulating GDF15 transcription levels and inducing ferroptosis in NPC cells.

• #47 Pathogenesis of Nasopharyngeal Carcinoma | SpringerLink

  https://link.springer.com/chapter/10.1007/978-1-4612-0405-3_55

  Pathogenesis of nasopharyngeal carcinoma (NPC) has not yet been fully understood, however, as a result of various studies conducted during last !0-!5 years it has become possible to have a better understanding of the process whereby a normal cell in the nasopharynx is driven to malignancy. […] It is considered that there are several different factors, in the form of genetic, Epstein-Barr virus (EBV), deficient immunosurveillant system and one or many other environmental factor/s, which could exert influence in bringing about the change.

• #48 Interplay of Viral Infection, Host Cell Factors and Tumor Microenvironment in the Pathogenesis of Nasopharyngeal Carcinoma

  https://www.mdpi.com/2072-6694/10/4/106

  Several EBV-encoded viral genes including LMP1, LMP2A/B, EBNA1 have been implicated in NPC pathogenesis by altering host cell signaling. […] Together with the other stromal cells, they form a unique TME which has been postulated to play an important role to support growth and progression of NPC cells in patients. […] Further investigation is needed to clearly define the components of NPC-Exo and the mechanisms that modify the TME.

• #49 Advances in the Pathogenesis and Therapeutic Strategies for Nasopharyngeal Carcinoma | Frontiers Research Topic

  https://www.frontiersin.org/research-topics/10572/advances-in-the-pathogenesis-and-therapeutic-strategies-for-nasopharyngeal-carcinoma/magazine

  In recent years there have been several developments in the field of nasopharyngeal carcinoma (NPC), including major advances in the pathogenesis, prognosis, and therapy. […] For example, there have been several studies exploring the molecular landscape of NPC that have identified crucial genomic changes that stimulate the development and progression of the disease; mechanisms underlying EBV infection and NPC development were further revealed, and plasma EBV DNA detection has been demonstrated to be useful for NPC screening. […] Biomarkers such as EBV DNA, DNA methylation, miRNAs, and mRNAs also have demonstrated their prognostic value and potential clinical applications. […] This Research Topic will provide high-quality evidence regarding the pathogenesis and therapeutic strategies of nasopharyngeal carcinoma, thus helping identify the required knowledge, tools, and therapies for advancing the management of NPC to the next level. […] 1. EBV infection and pathogenesis of NPC.

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