Interaction between Cigarette Smoke and Human Papillomavirus 16 E6/E7 Oncoproteins to Induce SOD2 Expression and DNA Damage in Head and Neck Cancer.

Even though epidemiological studies suggest that tobacco smoking and high-risk human papillomavirus (HR-HPV) infection are mutually exclusive risk factors for developing head and neck cancer (HNC), a portion of subjects who develop this heterogeneous group of cancers are both HPV-positive and smokers. Both carcinogenic factors are associated with increased oxidative stress (OS) and DNA damage. It has been suggested that superoxide dismutase 2 (SOD2) can be independently regulated by cigarette smoke and HPV, increasing adaptation to OS and tumor progression. In this study, we analyzed SOD2 levels and DNA damage in oral cells ectopically expressing HPV16 E6/E7 oncoproteins and exposed to cigarette smoke condensate (CSC). Additionally, we analyzed SOD2 transcripts in The Cancer Genome Atlas (TCGA) Head and Neck Cancer Database. We found that oral cells expressing HPV16 E6/E7 oncoproteins exposed to CSC synergistically increased SOD2 levels and DNA damage. Additionally, the SOD2 regulation by E6, occurs in an Akt1 and ATM-independent manner. This study suggests that HPV and cigarette smoke interaction in HNC promotes SOD2 alterations, leading to increased DNA damage and, in turn, contributing to development of a different clinical entity.

PI3K/AKT/mTOR Signaling Pathway in HPV-Driven Head and Neck Carcinogenesis: Therapeutic Implications.

High-risk human papillomaviruses (HR-HPVs) are the causal agents of cervical, anogenital and a subset of head and neck carcinomas (HNCs). Indeed, oropharyngeal cancers are a type of HNC highly associated with HR-HPV infections and constitute a specific clinical entity. The oncogenic mechanism of HR-HPV involves E6/E7 oncoprotein overexpression for promoting cell immortalization and transformation, through the downregulation of p53 and pRB tumor suppressor proteins, among other cellular targets. Additionally, E6/E7 proteins are involved in promoting PI3K/AKT/mTOR signaling pathway alterations. In this review, we address the relationship between HR-HPV and PI3K/AKT/mTOR signaling pathway activation in HNC with an emphasis on its therapeutic importance.

Epstein-Barr Virus Infection in Lung Cancer: Insights and Perspectives.

Lung cancer (LC) is the leading cause of cancer death worldwide. Tobacco smoke is the most frequent risk factor etiologically associated with LC, although exposures to other environmental factors such as arsenic, radon or asbestos are also involved. Additionally, the involvement of some viral infections such as high-risk human papillomaviruses (HR-HPVs), Merkel cell polyomavirus (MCPyV), Jaagsiekte Sheep Retrovirus (JSRV), John Cunningham Virus (JCV), and Epstein-Barr virus (EBV) has been suggested in LC, though an etiological relationship has not yet been established. EBV is a ubiquitous gamma herpesvirus causing persistent infections and some lymphoid and epithelial tumors. Since EBV is heterogeneously detected in LCs from different parts of the world, in this review we address the epidemiological and experimental evidence of a potential role of EBV. Considering this evidence, we propose mechanisms potentially involved in EBV-associated lung carcinogenesis. Additional studies are warranted to dissect the role of EBV in this very frequent malignancy.

High-Risk Human Papillomavirus Infection in Lung Cancer: Mechanisms and Perspectives.

Lung cancer is a very prevalent and heterogeneous group of malignancies, and most of them are etiologically associated with tobacco smoking. However, viral infections have been detected in lung carcinomas, with high-risk human papillomaviruses (HR-HPVs) being among them. The role of HR-HPVs in lung cancer has been considered to be controversial. This issue is due to the highly variable presence of this virus in lung carcinomas worldwide, and the low viral load frequently that is detected. In this review, we address the epidemiological and mechanistic findings regarding the role of HR-HPVs in lung cancer. Some mechanisms of HR-HPV-mediated lung carcinogenesis have been proposed, including (i) HPV works as an independent carcinogen in non-smoker subjects; (ii) HPV cooperates with carcinogenic compounds present in tobacco smoke; (iii) HPV promotes initial alterations being after cleared by the immune system through a "hit and run" mechanism. Additional research is warranted to clarify the role of HPV in lung cancer.

Characterization of High-Risk HPV/EBV Co-Presence in Pre-Malignant Cervical Lesions and Squamous Cell Carcinomas.

High-risk human papillomaviruses (HR-HPVs) are the etiological agents of cervical cancer. However, a low proportion of HR-HPV-infected women finally develop this cancer, which suggests the involvement of additional cofactors. Epstein−Barr virus (EBV) has been detected in cervical squamous cell carcinomas (SCCs) as well as in low- (LSIL) and high-grade (HSIL) squamous intraepithelial lesions, although its role is unknown. In this study, we characterized HR-HPV/EBV co-presence and viral gene expression in LSIL (n = 22), HSIL (n = 52), and SCC (n = 19) from Chilean women. Additionally, phenotypic changes were evaluated in cervical cancer cells ectopically expressing BamHI-A Rightward Frame 1 (BARF1). BARF1 is a lytic gene also expressed in EBV-positive epithelial tumors during the EBV latency program. HPV was detected in 6/22 (27.3%) LSIL, 38/52 (73.1%) HSIL, and 15/19 (78.9%) SCC cases (p < 0.001). On the other hand, EBV was detected in 16/22 (72.7%) LSIL, 27/52 (51.9%) HSIL, and 13/19 (68.4%) SCC cases (p = 0.177). HR-HPV/EBV co-presence was detected in 3/22 (13.6%) LSIL, 17/52 (32.7%) HSIL, and 11/19 (57.9%) SCC cases (p = 0.020). Additionally, BARF1 transcripts were detected in 37/55 (67.3%) of EBV positive cases and in 19/30 (63.3%) of HR-HPV/EBV positive cases. Increased proliferation, migration, and epithelial-mesenchymal transition (EMT) was observed in cervical cancer cells expressing BARF1. Thus, both EBV and BARF1 transcripts are detected in low- and high-grade cervical lesions as well as in cervical carcinomas. In addition, BARF1 can modulate the tumor behavior in cervical cancer cells, suggesting a role in increasing tumor aggressiveness.

Role of Epstein-Barr Virus and Human Papillomavirus Coinfection in Cervical Cancer: Epidemiology, Mechanisms and Perspectives.

High-risk human papillomavirus (HR-HPV) is etiologically associated with the development and progression of cervical cancer, although other factors are involved. Epstein-Barr virus (EBV) detection in premalignant and malignant tissues from uterine cervix has been widely reported; however, its contribution to cervical cancer development is still unclear. Here, a comprehensive analysis regarding EBV presence and its potential role in cervical cancer, the frequency of EBV/HR-HPV coinfection in uterine cervix and EBV infection in tissue-infiltrating lymphocytes were revised. Overall, reports suggest a potential link of EBV to the development of cervical carcinomas in two possible pathways: (1) Infecting epithelial cells, thus synergizing with HR-HPV (direct pathway), and/or (2) infecting tissue-infiltrating lymphocytes that could generate local immunosuppression (indirect pathway). In situ hybridization (ISH) and/or immunohistochemical methods are mandatory for discriminating the cell type infected by EBV. However, further studies are needed for a better understanding of the EBV/HR-HPV coinfection role in cervical carcinogenesis.

Merkel cell polyomavirus detected in head and neck carcinomas from Chile.

BACKGROUND: The role of human polyomaviruses (HPyVs) in epithelial tumors such as head and neck carcinomas (HNSCCs) including oral and oropharyngeal carcinomas has not been established. In this study, we evaluated for the first time the presence of Merkel cell polyomavirus (MCPyV), BK human polyomavirus (BKPyV), and JC human polyomavirus (JCPyV) in HNSCCs from Chilean subjects. METHODS: One hundred and twenty HNSCCs were analyzed for the presence of MCPyV, BKPyV and JCPyV using real-time polymerase chain reaction procedures. In addition, 54 oral brushes from age- and sex-paired subjects were analyzed. RESULTS: Of the total of 120 HNSCCs, 15 were positive for MCPyV (12.5%). Only one case was positive for BKPyV (0.8%) and none for JCPyV (0%). In subjects without cancer, only one case (1.8%) resulted positive for MCPyV and none for JCPyV and BKPyV. MCPyV was associated with HNSCCs (p = 0.0239; OR = 7.571; 95% CI: 1.192-81.46). No association was found between age (p = 0.1996), gender (p = 0.7111) or differentiation status (p > 0.9999) and MCPyV presence in HNSCCs. CONCLUSIONS: MCPyVs were detected in HNSCCs from Chilean patients and were not detected in oral brushes from patients without cancer. More studies are warranted for defining an etiological role and clinical/molecular consequences of these viruses in HNSCCs.

Curcumin decreases epithelial­mesenchymal transition by a Pirin­dependent mechanism in cervical cancer cells.

Curcumin is a natural antioxidant polyphenol, which decreases epithelial­mesenchymal transition (EMT) and cell migration in cervical cancer cells. However, the mechanism by which such a decrease occurs is unclear. It is well established that cervical cancer can be caused by high­risk human papillomavirus (HPV), which overexpresses E6 and E7 oncoproteins. Recent findings have suggested that viral oncoproteins regulate the expression of Pirin, which is an oxidative stress sensor involved in EMT and cell migration. Molecular markers associated with EMT, pirin and HPV were evaluated using reverse transcription­reverse quantitative PCR and western blotting. In addition, the migratory ability of cells was evaluated using a Transwell assay. In order to evaluate the role of Pirin in curcumin­mediated inhibition of EMT, SiHa cervical carcinoma cells, which contain two integrated copies of HPV16, were exposed to curcumin. Cell migration, and the expression levels of EMT biomarkers and the pirin protein, which is a product of the PIR gene, were subsequently evaluated. The results demonstrated a significant decrease in EMT following exposure to 20 µM curcumin for 72 h. This finding was supported by a decrease in the protein expression levels of N­cadherin, Vimentin and Slug. Furthermore, it was observed that PIR expression and Pirin protein levels were significantly decreased when SiHa cells were exposed to curcumin. Subsequently, to analyze the effects of Pirin on EMT, SiHa cells were transfected with a small interfering RNA (siRNA) to knockdown PIR. A significant increase in E­cadherin mRNA expression and a decrease in N­cadherin protein expression were observed. In addition, a similar decrease was observed when SiHa cells were exposed to both PIR siRNA and curcumin. Finally, a significant decrease in SiHa cell migration was observed in the presence of 20 µM curcumin compared with in the control group. These findings suggested that curcumin may decrease EMT, at least in part by a Pirin­dependent mechanism. Therefore, Pirin protein may be an important pharmacological target for cervical cancer treatment.

Detección del virus Epstein Barr en escolares adolescentes en la ciudad de Cali, Colombia / Detection of epstein barr virus in adolescent students in the city of cali, colombia

Objetivo: Detectar el virus Epstein-Barr en estudiantes de secundaria entre los 14 y 17 años de la ciudad de Cali, Colombia y su posible asociación con la edad, sexo y grado escolar. Métodos: Estudio retrospectivo de corte transversal en donde se analizaron 374 muestras de saliva, tomadas entre el año 2015 y 2016, mediante PCR convencional y PCR en Tiempo real. Se evalúo la asociación entre la detección del ADN viral y las características demográficas, además de un análisis de razón de oportunidades para evaluar la medida de la asociación. Resultados: El ADN viral fue detectado en el 45% (167/374) de las muestras orales, encontrándose una presencia viral mayor en los escolares de los grados octavo y noveno (p=0,004); en donde los estudiantes de 14 años presentaron un riesgo de 2,4 veces mayor para la detección del virus (IC 95%:1,12-4,9) en comparación con los estudias de más edad. Conclusión: En el presente estudio se evidencio la exposición del VEB en la cavidad oral de estudiantes de secundaria, lo cual hace necesario que se tomen acciones de vigilancia que permitan monitorear las implicaciones de estos hallazgos en la salud de los escolares.

Objective: To detect the Epstein Barr virus in adolescent students between 14 and 17 years old in the city of Cali, Colombia and its possible association with age, gender and school grade. Methods: Retrospective cross-sectional study where 374 mouthwash samples collected between the years 2015 and 2016 was analyzed through conventional and real-time PCR. Association between viral DNA detection and sociodemographic characteristics were evaluated. The odds ratio analysis was used to assess the extent of this association. Results: The viral DNA was present in 45% (167/374) of the samples, with a higher DNA detection in the students of eighth and ninth grades (p=0.004); where the 14 years old students present a 2.4 times higher risk of detecting the virus (IC 95%: 1,12-4.9) in comparison with older students. Conclusion: In the present study, the Epstein Barr virus exposition in the oral cavity was evidenced, which make necessary to take actions on surveillance that allow monitoring the implications of these fndings in the teenage student's health.