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12 pages, 1349 KiB

Open AccessArticle

Epstein–Barr Virus LMP1 Induces Soluble PD-L1 in Nasopharyngeal Carcinoma

by Kina Kase, Satoru Kondo, Naohiro Wakisaka, Hirotomo Dochi, Harue Mizokami, Eiji Kobayashi, Makoto Kano, Takeshi Komori, Nobuyuki Hirai, Takayoshi Ueno, Yosuke Nakanishi, Miyako Hatano, Kazuhira Endo, Makiko Moriyama-Kita, Hisashi Sugimoto and Tomokazu Yoshizaki

Microorganisms 2021, 9(3), 603; https://doi.org/10.3390/microorganisms9030603 - 15 Mar 2021

Cited by 16 | Viewed by 2887

Abstract

Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated malignancy. The principal oncogene of EBV, latent membrane protein 1 (LMP1), induces the expression of programmed death-ligand 1 (PD-L1), which is an immunosuppressive transmembrane protein and a promising therapeutic target for various malignancies. Recent studies [...] Read more.

Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated malignancy. The principal oncogene of EBV, latent membrane protein 1 (LMP1), induces the expression of programmed death-ligand 1 (PD-L1), which is an immunosuppressive transmembrane protein and a promising therapeutic target for various malignancies. Recent studies have revealed an association between the level of soluble PD-L1 (sPD-L1) and disease progression. However, the role of sPD-L1 in NPC or its relevance to LMP1 has not been elucidated. This study aimed to examine whether LMP1 induces sPD-L1 in vitro and analyze the clinical relevance of LMP1, PD-L1, and sPD-L1 in NPC patients. Analysis of nasopharyngeal cell lines revealed that LMP1 induces both cellular PD-L1 and sPD-L1. Analysis of biopsy specimens from 32 NPC patients revealed that LMP1 expression was significantly correlated with PD-L1 expression. Finally, the serum sPD-L1 level in NPC patients was higher than that in the controls. Moreover, the sPD-L1 level in the advanced stage was higher than that in the early stage. However, LMP1 expression, PD-L1 expression, and sPD-L1 levels were not associated with prognosis. These results suggest that LMP1 induces both sPD-L1 and PD-L1, which are associated with NPC progression. Full article

(This article belongs to the Special Issue Pathogenic Role of Virus Infection in Head and Neck Tumors)

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Latent membrane protein 1 (LMP1) induces both cellular programmed death-ligand 1 (PD-L1) protein and soluble PD-L1 (sPD-L1). (Top lane) The media of both NP69T and NP69T-LMP1 cells were analyzed with western blotting for detecting PD-L1 levels. (Second, third, and fourth lane) Western blotting of PD-L1 and LMP1 in NP69T and NP69T-LMP1 cells. Total cell lysates and medium were collected from cell culture at 48 h. The harvested medium was concentrated to 50 fold. Full article ">Figure 2
LMP1 and PD-L1 expression in NPC tissue samples. The specimens were immunostained with LMP1 and PD-L1 antibody. Brown staining indicates positive cell membrane expression of LMP1 (A) and PD-L1 (B). Dual fluorescence immunostaining of LMP1 (C) and PD-L1 (D), and DAPI (E) in NPC tissue samples. (F) Merged image of LMP1 and PD-L1. White arrowheads indicate the colocalization of LMP1 and PD-L1. Original magnifications (A,B): ×100, inset figures: ×400, scale bar: 100 μm. Original magnifications (C–F): ×600. Full article ">Figure 3
Expression of PD-L1 (TPS and CPS) corelates with LMP1 in NPC tissue samples. Data were analyzed using the Spearman rank correlation coefficient. Statistical significance was defined as a p-value less than 0.05. (A) Relationship between LMP1 expression score and TPS (p = 0.023, r = 0.402). (B) Relationship between LMP1 expression score and CPS (p = 0.008, r = 0.461). Full article ">Figure 4
Elevated serum sPD-L1 levels in patients with NPC compared to those in the controls. There was a significant difference in sPD-L1 levels between the controls and the patients with NPC (p = 0.031). p-value was calculated using the Mann–Whitney U-test. NPC: nasopharyngeal carcinoma, sPD-L1: soluble PD-L1. Full article ">Figure 5
Kaplan–Meier curves of progression-free survival (PFS) in patients with NPC. The p-value was calculated using log-rank test. (A) Kaplan–Meier curves of LMP1-positive (≥LMP1 expression score 10%) and LMP1-negative (<LMP1 expression score 10%) samples. (B) Kaplan–Meier curves of PD-L1 TPS-positive (≥10%) and PD-L1 TPS-negative (<10%) samples. (C) Kaplan–Meier curves of PD-L1 CPS-positive (≥10%) and PD-L1 CPS-negative (<10%) samples. (D) Kaplan–Meier curves of sPD-L1-positive (≥0.1 ng/mL) and sPD-L1-negative (<0.1 ng/mL) samples. * p < 0.05. LMP1: latent membrane protein 1, TPS: tumor proportion score, CPS: combined positive score, sPD-L1: soluble PD-L1. Full article ">

18 pages, 3708 KiB

Open AccessArticle

Coordinated Expression of HPV-6 Genes with Predominant E4 and E5 Expression in Laryngeal Papilloma

by Taro Ikegami, Hitoshi Hirakawa, Narutoshi Tsukahara, Akikazu Murakami, Norimoto Kise, Asanori Kiyuna, Takayoshi Kosugi, Shinya Agena, Hidetoshi Kinjyo, Narumi Hasegawa, Masatomo Touyama, Shunsuke Kondo, Hiroyuki Maeda, Mikio Suzuki and Akira Ganaha

Microorganisms 2021, 9(3), 520; https://doi.org/10.3390/microorganisms9030520 - 3 Mar 2021

Cited by 11 | Viewed by 3282

Abstract

Laryngeal papilloma (LP) associated with human papillomavirus (HPV)-6 or -11 infection shows aggressive growth. However, the detailed molecular mechanism of virus-driven tumorigenesis has not been uncovered fully. HPV-6 viral gene expression and dynamic alterations were investigated with in situ localization of viral DNA [...] Read more.

Laryngeal papilloma (LP) associated with human papillomavirus (HPV)-6 or -11 infection shows aggressive growth. However, the detailed molecular mechanism of virus-driven tumorigenesis has not been uncovered fully. HPV-6 viral gene expression and dynamic alterations were investigated with in situ localization of viral DNA and RNA in 13 patients with HPV-6-infected laryngeal papilloma. The average viral load was 4.80 × 10⁵ ± 1.86 × 10⁵ copies/ng DNA. E4, E5a, and E5b mRNAs accounted for 96% of the expression of 9 mRNAs. The alteration of viral DNA load during recurrence paralleled the mRNA expression levels, and the expression of all mRNAs showed a similar curve. E4, E5a, and E5b were expressed in the middle to upper part of the epithelium and were co-expressed in the same cells. E4 immunohistochemistry demonstrated an extensively positive reaction in the upper cell layer in accordance with E4 mRNA expression. These results suggest that individual viral genes are coordinately expressed for viral replication, virus release, and immunosurveillance avoidance. The newly developed E4-specific monoclonal antibody can be applied to further functional studies and clinical applications such as targeted molecular therapies. Full article

(This article belongs to the Special Issue Pathogenic Role of Virus Infection in Head and Neck Tumors)

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Schema of human papillomavirus-6 (HPV-6) genes and information of plasmid clones and RNA in situ hybridization probes used in this study. Full article ">Figure 2
HPV-6-positive cells in LP by DNA-ISH. (a) The basal cells and middle to upper third layers of LP showed a positive reaction. Bar = 50 μm. (b) The positive reaction was observed in all LP layers. Bar = 50 μm. Full article ">Figure 3
HPV-6 mRNA expression in individual cases and summation of all cases. (a) Viral mRNA expression in each case. There were some differences in the proportion of E4, E5a, and E5b expression. However, these 3 mRNAs were predominant compared with the other mRNAs examined. (b) Proportion of mRNA expression. E4 was the most prevalent gene among the 9 viral mRNAs. Full article ">Figure 4
Alteration of mRNA levels, DNA viral load and Derkay score during long-term observation in patient 10. The viral DNA load alteration curve was similar to the mRNA expression curve. Full article ">Figure 5
HPV mRNA expression in LP by RNA-ISH. Representative mRNA expression of (a) E6; (b) E2; (c) E4; (d) E5a; (e) E5b. E4 and E5a were markedly expressed in the upper third of LP. Bar = 100 μm. Full article ">Figure 6
E4 and E5a, and E4 and E5b expression detected by double fluorescence RNA-ISH. (a) Double staining of E4 and E5a in LP (bar = 100 μm). (b) E4 and E5b in LP (bar = 50 μm). E4 and E5a and E4 and E5b mRNAs were co-expressed in the same LP cells. Full article ">Figure 7
Immunohistochemistry for HPV-6 E4 in HPV-6-infected (a,b) and HPV-11-infected (c,d) LP. (a) Immunohistochemistry for HPV-6 E4 (low magnification) in HPV-6-infected LP (bar = 200 μm). (b) Immunohistochemistry for HPV-6 E4 (high magnification) in HPV-6-infected LP (bar = 50 μm). (c) Immunohistochemistry for HPV-6 E4 (low magnification) in HPV-11-infected LP (bar = 200 μm). (d) Immunohistochemistry for HPV-6 E4 (low high magnification) in HPV-11-infected LP (bar = 50 μm). Strong immunoreactivity was observed in (a,b), but there were no positive reactions in (c,d). Full article ">

15 pages, 8510 KiB

Open AccessArticle

G Protein-Coupled Receptor Genes, PTGDR1, PTGDR2, and PTGIR, Are Candidate Epigenetic Biomarkers and Predictors for Treated Patients with HPV-Associated Oropharyngeal Cancer

by Kiyoshi Misawa, Atsushi Imai, Takeharu Kanazawa, Masato Mima, Satoshi Yamada, Daiki Mochizuki, Taiki Yamada, Daichi Shinmura, Ryuji Ishikawa, Jyunya Kita, Yuki Yamaguchi, Yuki Misawa and Hiroyuki Mineta

Microorganisms 2020, 8(10), 1504; https://doi.org/10.3390/microorganisms8101504 - 29 Sep 2020

Cited by 10 | Viewed by 2883

Abstract

Differences in the biology of human papillomavirus (HPV)-associated oropharyngeal cancers (OPCs) and HPV-negative OPCs may have implications in patient management. Early detection is imperative to reduce HPV-associated OPC mortality. Circulating tumor DNA (ctDNA) can potentially serve as a biomarker for monitoring clinically relevant [...] Read more.

Differences in the biology of human papillomavirus (HPV)-associated oropharyngeal cancers (OPCs) and HPV-negative OPCs may have implications in patient management. Early detection is imperative to reduce HPV-associated OPC mortality. Circulating tumor DNA (ctDNA) can potentially serve as a biomarker for monitoring clinically relevant cancer-related genetic and epigenetic modifications. We analyzed the methylation status of 24 G protein-coupled receptor (GPCR) genes in verification (85 OPC primary samples) and validation (8 OPC ctDNA samples) studies using quantitative methylation-specific polymerase chain reaction (Q-MSP). The Q-MSP-based verification study with 85 OPC primary samples revealed the GPCR genes that were significantly associated with recurrence in high methylation groups (≥14 methylated genes) with OPC and HPV-associated OPC (p < 0.001). In the Kaplan–Meier estimate and multivariate Cox proportional hazard analyses, 13 GPCR genes were significantly related to increased recurrence in the methylation group. Furthermore, the validation study on ctDNA showed that three of these genes (Prostaglandin D2 receptor 1: PTGDR1, Prostaglandin D2 receptor 2: PTGDR2, and Prostaglandin I2 Receptor: PTGIR) had a prediction performance as emerging biomarkers. We characterized the relationship between the methylation status of GPCR genes and outcomes in HPV-associated OPC. Our results highlight the potential utility of ctDNA methylation-based detection for the clinical management of HPV-associated OPC. Full article

(This article belongs to the Special Issue Pathogenic Role of Virus Infection in Head and Neck Tumors)

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Methylation frequencies for 24 G protein-coupled receptor (GPCR) genes in oropharyngeal cancer (OPC) tissue samples. (A) Comparison of methylation statuses of the promoters of 24 GPCR genes in patients with human papillomavirus (HPV)-associated and HPV-negative OPC. (B) Bar graph showing methylation frequencies (%) of 24 GPCR genes in the verification cohort. Blue bars, samples of HPV-associated cases; orange bars, samples of HPV-negative cases. (C) The mean methylation index values for HPV-associated and HPV-negative groups have been compared using the Student’s t-test. Full article ">Figure 2
Association between methylation index and selected clinical parameters. The mean methylation index values for various groups have been compared using the Student’s t-test to detect any association between methylation index and selected epidemiologic and clinical characteristics: (A) Eighty-five full panel cases. No differences have been noted with respect to clinical characteristics, (B) HPV-associated OPC, (C) HPV-negative OPC. Mean and standard deviation (SD) have been also indicated, and statistical comparisons between groups are depicted. * p < 0.05 indicates the statistical significance. Full article ">Figure 3
Kaplan–Meier survival curves for patients with OPC based on GPCR gene methylation status. Disease-free survival based on (A) methylation status in full cases (n = 85), (B) HPV status in full cases (n = 85), (C) methylation status in HPV-associated OPC cases (n = 48), (D) methylation status in HPV-negative OPC cases (n = 37). *p < 0.05. Full article ">Figure 4
Kaplan–Meier survival curves for 48 patients with HPV-associated oropharyngeal cancer according to the methylation statuses of 24 target genes disease free survival (DFS) for (A) GALR1, (B) GALR2, (C) GHSR, (D) HCRTR1, (E) HCRTR2, (F) MLNR, (G) NMUR1, (H) NPY1R, (I) NPY2R, (J) NPY4R, (K) NPY5R, (L) NTSR1, (M) NTSR2, (N) PTGDR1, (O) PTGDR2, (P) PTGER1, (Q) PTGER2, (R) PTGER3, (S) PTGER4, (T) PTGFR, (U) PTGIR, (V) SSTR1, (W) TACR1, and (X) TBXA2R for methylated (red lines) and unmethylated (blue lines) genes. A value of p < 0.05 has been considered statistically significant. Full article ">Figure 5
Risk of recurrence based on 24 GPCR genes’ odds ratios (OR) for recurrence were determined using a Cox proportional hazard model adjusted for age (≥70 vs. <70 years), sex, alcohol intake, smoking status, and tumor stage (I vs. II–IV). (A) Full panel of OPC (n = 85), (B) HPV-associated OPC (n = 48), (C) HPV-negative OPC (n = 37). OR: odds ratio. CI: confidence interval. * p < 0.05. Full article ">Figure 6
Validation analysis of methylation status in clinical primary samples and paired ctDNA samples. Comparison of methylation statuses represents the methylation status of these 13 markers in (A) 8 primary samples, (B) ctDNA isolated from the same patients before treatment as above, and (C) post-treatment. Full article ">

12 pages, 2407 KiB

Open AccessArticle

Influences of Semaphorin 3A Expression on Clinicopathological Features, Human Papillomavirus Status, and Prognosis in Oropharyngeal Carcinoma

by Hai Thanh Pham, Satoru Kondo, Kazuhira Endo, Naohiro Wakisaka, Yoshitaka Aoki, Yosuke Nakanishi, Kina Kase, Harue Mizokami, Makoto Kano, Takayoshi Ueno, Miyako Hatano, Makiko Moriyama-Kita, Hisashi Sugimoto and Tomokazu Yoshizaki

Microorganisms 2020, 8(9), 1286; https://doi.org/10.3390/microorganisms8091286 - 22 Aug 2020

Cited by 3 | Viewed by 2726

Abstract

Human papillomavirus (HPV) infection is now identified as a major etiologic factor for oropharyngeal cancer (OPC), and HPV positivity is well established better prognostic marker in OPC. Now, predictable markers for the prognosis of the patients who are stratified by HPV has been [...] Read more.

Human papillomavirus (HPV) infection is now identified as a major etiologic factor for oropharyngeal cancer (OPC), and HPV positivity is well established better prognostic marker in OPC. Now, predictable markers for the prognosis of the patients who are stratified by HPV has been investigated in. Semaphorin 3A (SEMA3A) is a well-known axon guidance molecule in the nervous system. It is also known as a tumor suppressor in various cancers. In the present study, we examined the relationships between SEMA3A and clinicopathologic features, especially HPV status, and neoangiogenesis, and its prognostic significance for OPC patients. Thirty-two OPC patients and 17 normal patients were analyzed for SEMA3A expression by immunohistochemical analysis. We also analyzed 22 OPC specimens for CD34 expression as a marker of neoangiogenesis. SEMA3A was significantly downregulated in OPC compared with chronic tonsillitis tissues (p = 0.005). SEMA3A expression was negatively correlated with CD34 expression (r = −0.466, p = 0.033). Moreover, the higher SEMA3A expression cohort showed better survival than the lower SEMA3A expression cohort regardless of HPV status (p = 0.035). These results suggest that SEMA3A expression is a prognostic marker for survival regardless of HPV status and is associated with anti-angiogenesis in OPC. Full article

(This article belongs to the Special Issue Pathogenic Role of Virus Infection in Head and Neck Tumors)

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(A). SEMA3A in chronic tonsillitis tissue (magnification × 100, scale bar shows 100 µm, lower right rectangle × 400, scale bar shows 50 um). (B,C). SEMA3A was detected primarily in the cytoplasm of tumor cells (magnification × 100, scale bar shows 100 µm; lower right rectangle × 400, scale bar shows 50 µm) (B). Low level of SEMA3A expression (C). High level of SEMA3A expression. Full article ">Figure 2
Comparison of different Kaplan–Meier curves for overall survival for patients grouped by immunohistochemistry levels of SEMA3A. (A) Kaplan–Meier curves for overall survival (OS) of the 32 OPC patients. (B) Kaplan–Meier curves for OS for OPC patients with low and high levels of SEMA3A expression (p = 0.035). (C) Kaplan–Meier curves for OS in patients who were HPV (+) with low and high levels of SEMA3A expression (p = 0.024). (D). Kaplan–Meier curves for OS in patients who were HPV (−) with low and high levels of SEMA3A expression (p = 0.016). Full article ">Figure 3
(A) Immunohistochemical detection of CD34 protein expression in OPC tissues (magnification × 100, scale bar shows 100 µm; lower right rectangle × 400, scale bar shows 50 µm). (B) Relationship between SEMA3A expression and MVD. A Spearman correlation test was performed between SEMA3A expression and CD34 (microvessel density). There was a significant negative correlation between SEMA3A and CD34 (p = 0.033, r = −0.466). Full article ">

Review

Jump to: Research

19 pages, 1642 KiB

Open AccessReview

Extranodal NK/T-Cell Lymphoma, Nasal Type: Genetic, Biologic, and Clinical Aspects with a Central Focus on Epstein–Barr Virus Relation

by Miki Takahara, Takumi Kumai, Kan Kishibe, Toshihiro Nagato and Yasuaki Harabuchi

Microorganisms 2021, 9(7), 1381; https://doi.org/10.3390/microorganisms9071381 - 25 Jun 2021

Cited by 14 | Viewed by 6403

Abstract

Extranodal NK/T-Cell Lymphoma, nasal type (ENKTL-NT) has some salient aspects. The lymphoma is commonly seen in Eastern Asia, has progressive necrotic lesions in the nasal cavity, makes midfacial destructive lesions, and shows poor prognosis. The lymphoma cell is originated from either NK- or [...] Read more.

Extranodal NK/T-Cell Lymphoma, nasal type (ENKTL-NT) has some salient aspects. The lymphoma is commonly seen in Eastern Asia, has progressive necrotic lesions in the nasal cavity, makes midfacial destructive lesions, and shows poor prognosis. The lymphoma cell is originated from either NK- or γδ T-cells, which express CD56. Since the authors first demonstrated the existence of Epstein–Barr virus (EBV) DNA and EBV oncogenic proteins in lymphoma cells, ENKTL-NT has been recognized as an EBV-associated malignancy. Because the angiocentric and polymorphous lymphoma cells are mixed with inflammatory cells on a necrotic background, the diagnosis of ENKTL-NT requires CD56 immunostaining and EBER in situ hybridization. In addition, serum the EBV DNA level is useful for the diagnosis and monitoring of ENKTL-NT. Although ENKTL-NT is refractory lymphoma, the prognosis is improved by the development of therapies such as concomitant chemoradiotherapy. The basic research reveals that a wide variety of intracellular/cell surface molecules, cytokines, chemokines, and micro RNAs are involved in lymphomagenesis, and some of them are related to EBV. Understanding lymphoma behavior introduces new therapeutic strategies, such as the usage of immune checkpoint inhibitors, peptide vaccines, and molecular targeting therapy. This review addresses recent advances in basic and clinical aspects of ENKTL-NT, especially its relation to EBV features. Full article

(This article belongs to the Special Issue Pathogenic Role of Virus Infection in Head and Neck Tumors)

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11 pages, 889 KiB

Open AccessReview

Virus-Associated Biomarkers in Oropharyngeal and Nasopharyngeal Cancers and Recurrent Respiratory Papillomatosis

by Shigeyuki Murono

Microorganisms 2021, 9(6), 1150; https://doi.org/10.3390/microorganisms9061150 - 27 May 2021

Cited by 1 | Viewed by 2852

Abstract

Nasopharyngeal cancer (NPC) is known to be associated with Epstein–Barr virus (EBV). Pre-treatment and post-treatment detection of plasma cell-free EBV DNA has been shown to be useful as a diagnostic as well as a prognostic factor in NPC. On the other hand, the [...] Read more.

Nasopharyngeal cancer (NPC) is known to be associated with Epstein–Barr virus (EBV). Pre-treatment and post-treatment detection of plasma cell-free EBV DNA has been shown to be useful as a diagnostic as well as a prognostic factor in NPC. On the other hand, the incidence of human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) is increasing. In contrast to cervical cancer, which is classically known to be an HPV-associated malignancy, HPV testing is not clinically applied for OPC, except for p16 immunostaining as a surrogate marker of HPV infection. One of the major characteristics of HPV-associated OPC is its association with a good prognosis compared with non-HPV-associated OPC. However, some patients still have a poor prognosis. Another characteristic of HPV-associated OPC is the distinct risk factor of high sexual activity. Establishing a biomarker for the prediction of the prognosis before and/or after initial treatment, as well as for diagnosis in populations at high risk, is of marked interest. With this background, HPV DNA detection in plasma and oral rinses has become an area of focus. In this review, the current significance of HPV DNA detection in plasma and oral rinse samples, as well as serum HPV antibody levels, is evaluated. Full article

(This article belongs to the Special Issue Pathogenic Role of Virus Infection in Head and Neck Tumors)

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14 pages, 2929 KiB

Open AccessReview

Pathogenic Role of Immune Evasion and Integration of Human Papillomavirus in Oropharyngeal Cancer

by Takashi Hatano, Daisuke Sano, Hideaki Takahashi and Nobuhiko Oridate

Microorganisms 2021, 9(5), 891; https://doi.org/10.3390/microorganisms9050891 - 21 Apr 2021

Cited by 10 | Viewed by 3629

Abstract

The incidence of oropharyngeal cancer (OPC) is increasing remarkably among all head and neck cancers, mainly due to its association with the human papillomavirus (HPV). Most HPVs are eliminated by the host’s immune system; however, because HPV has developed an effective immune evasion [...] Read more.

The incidence of oropharyngeal cancer (OPC) is increasing remarkably among all head and neck cancers, mainly due to its association with the human papillomavirus (HPV). Most HPVs are eliminated by the host’s immune system; however, because HPV has developed an effective immune evasion mechanism to complete its replication cycle, a small number of HPVs are not eliminated, leading to persistent infection. Moreover, during the oncogenic process, the extrachromosomal HPV genome often becomes integrated into the host genome. Integration involves the induction and high expression of E6 and E7, leading to cell cycle activation and increased genomic instability in the host. Therefore, integration is an important event in oncogenesis, although the associated mechanism remains unclear, especially in HPV-OPC. In this review, we summarize the current knowledge on HPV-mediated carcinogenesis, with special emphasis on immune evasion and integration mechanisms, which are crucial for oncogenesis. Full article

(This article belongs to the Special Issue Pathogenic Role of Virus Infection in Head and Neck Tumors)

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Genome organization of human papillomavirus (HPV) 16 and function of viral gene products. Schematic representation of the HPV16 genome shows location of early (E) and late (L) genes, and of the long control region (LCR). Full article ">Figure 2
(a) Role of human papillomavirus (HPV) E7 oncoprotein in the progression to cancer. HR HPV E7 protein targets retinoblastoma (Rb) family members for degradation, resulting in the release and activation of E2F transcription factors that drive the expression of S phase genes as well as induction of hyperproliferation. E7 can also induce cellular proliferation through deregulation of cyclin-dependent kinase (CDK) inhibitors p21 and p27, leading to direct activation of CDK2. Degradation of Rb family members by HPV E7 protein leads to p16 overexpression, inhibiting the ability of CDK4 to interact with cyclin D and stimulating passage through the G1 phase of the cell cycle. (b) Role of HPV E6 oncoprotein in the progression to cancer. HR-HPV E6 inhibits p53-dependent growth arrest, resulting in the induction of genomic instability and the accumulation of cellular mutations. HR HPV E6 protein binds to cellular ubiquitin ligase E6AP to form a trimeric complex with p53, leading to the ubiquitylation and proteasomal degradation of p53 and the inhibition of p21. E6 also activates telomerase reverse transcriptase (TERT) and telomerase, resulting in cell proliferation and promoting immortalization. Full article ">Figure 3
(a) Integration breakpoint distribution in human chromosomes and HPV16 genome represented by Circos plots of the UCSC:SCC090 genome. (b) Breakpoint distribution percentage in HPV16 cell lines (UCSC:SCC090, UCSC:SCC152, UCSC:SCC154). (c) Categories of viral-host breakpoints; (1) Seamless transition with defined breakpoint. (2) Insertion; nucleotides that align to neither reference genome. (3) Breakpoint microhomology; nucleotides that align to both reference genomes. Full article ">

14 pages, 1486 KiB

Open AccessReview

DNA Methylation and HPV-Associated Head and Neck Cancer

by Takuya Nakagawa, Tomoya Kurokawa, Masato Mima, Sakiko Imamoto, Harue Mizokami, Satoru Kondo, Yoshitaka Okamoto, Kiyoshi Misawa, Toyoyuki Hanazawa and Atsushi Kaneda

Microorganisms 2021, 9(4), 801; https://doi.org/10.3390/microorganisms9040801 - 10 Apr 2021

Cited by 19 | Viewed by 4521

Abstract

Head and neck squamous cell carcinoma (HNSCC), especially oropharyngeal squamous cell carcinoma (OPSCC), has recently been found to be significantly associated with human papillomavirus (HPV) infection. The incidence of OPSCC has been increasing and surpassed the number of cervical cancer cases in the [...] Read more.

Head and neck squamous cell carcinoma (HNSCC), especially oropharyngeal squamous cell carcinoma (OPSCC), has recently been found to be significantly associated with human papillomavirus (HPV) infection. The incidence of OPSCC has been increasing and surpassed the number of cervical cancer cases in the United States. Although HPV-associated OPSCC has a relatively better prognosis than HPV-negative cancer, approximately 20% of HPV-associated HNSCC patients show a poor prognosis or therapeutic response, and the molecular mechanism behind this outcome in the intermediate-risk group is yet to be elucidated. These biological differences between HPV-associated HNSCC and HPV-negative HNSCC are partly explained by the differences in mutation patterns. However, recent reports have revealed that epigenetic dysregulation, such as dysregulated DNA methylation, is a strikingly common pathological feature of human malignancy. Notably, viral infections can induce aberrant DNA methylation, leading to carcinogenesis, and HPV-associated HNSCC cases tend to harbor a higher amount of aberrantly methylated DNA than HPV-negative HNSCC cases. Furthermore, recent comprehensive genome-wide DNA-methylation analyses with large cohorts have revealed that a sub-group of HPV-associated HNSCC correlates with increased DNA methylation. Accordingly, in this review, we provide an overview of the relationship between DNA methylation and HPV-associated HNSCC. Full article

(This article belongs to the Special Issue Pathogenic Role of Virus Infection in Head and Neck Tumors)

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Transcriptional repression by promoter DNA hypermethylation and histone modifications. In normal cells, the CpG islands of promoter regions are open chromatin and generally unmethylated. Gene transcription is activated by transcriptional factors with H3K27ac (left). In cancer cells, the CpG islands in the promoter regions are hypermethylated, constructing heterochromatin with H3K27me3 and H3K9me3, which suppresses gene transcription (right). Abbreviations: H3K27me3, trimethylation of lysine 27 on histone 3; H3K9me3, trimethylation of lysine 9 on histone 3; H3K27ac, acetylation of lysine 27 on histone 3. Full article ">Figure 2
The molecular mechanism of induction of DNA methylation in human papillomavirus (HPV)--associated head and neck squamous cell carcinoma (HNSCC). Wild-type p53 negatively regulates DNA methyltransferase 1 (DNMT1). HPV E6 oncoprotein cause degradation of p53 and it results in the upregulation of DNMT1 (left). HPV E7 oncoprotein forms a complex with DNMT1 and results in DNMT1 upregulation (middle). MYC is upregulated in HPV-associated HNSCC and recruit DNMT3B (right). Full article ">Figure 3
Distribution of DNA methylation pattern and biological characteristics in HPV-associated OPSCC. Genome-wide DNA methylation analysis revealed two types of DNA methylation patterns in HPV-associated OPSCC. In high DNA methylation subtype, HPV genome integration (−), episomal HPV (+), high expression of E2/E4/E5, and better prognosis compared to the intermediate DNA methylation subtype and CREBBP mutation (+) were previously reported. In intermediate DNA methylation subtype, HPV genome integration (+), episomal HPV (−), high expression of E6/E7, and worse prognosis compared to the high DNA methylation subtype were reported. Full article ">

11 pages, 1066 KiB

Open AccessReview

Chronic Active Epstein–Barr Virus Infection: The Elucidation of the Pathophysiology and the Development of Therapeutic Methods

by Ayako Arai

Microorganisms 2021, 9(1), 180; https://doi.org/10.3390/microorganisms9010180 - 15 Jan 2021

Cited by 21 | Viewed by 7127

Abstract

Chronic active Epstein–Barr virus infection (CAEBV) is a disease where Epstein–Barr virus (EBV)-infected T- or NK-cells are activated and proliferate clonally. The symptoms of this dual-faced disease include systemic inflammation and multiple organ failures caused by the invasion of infected cells: inflammation and [...] Read more.

Chronic active Epstein–Barr virus infection (CAEBV) is a disease where Epstein–Barr virus (EBV)-infected T- or NK-cells are activated and proliferate clonally. The symptoms of this dual-faced disease include systemic inflammation and multiple organ failures caused by the invasion of infected cells: inflammation and neoplasm. At present, the only effective treatment strategy to eradicate EBV-infected cells is allogeneic stem cell transplantation. Lately, the investigation into the disease’s pathogenic mechanism and pathophysiology has been advancing. In this review, I will evaluate the new definition in the 2017 WHO classification, present the advancements in the study of CAEBV, and unfold the future direction. Full article

(This article belongs to the Special Issue Pathogenic Role of Virus Infection in Head and Neck Tumors)

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