Human Papillomavirus-Related Cancers.
Li Yanyun,Xu Congjian
Advances in experimental medicine and biology
Human papillomavirus (HPV) infection is associated with several cancers such as cancer in the cervix, vagina, and vulva and oropharyngeal, anal, penile, and cutaneous carcinomas, which is regarded as a great public health concern. The association between HPV is the strongest with cervical cancer because almost all such malignancies contain viral DNA, notably HPV types 16 and 18. The present chapter summarizes recent progresses of the HPV-associated cancers regarding epidemiology, molecular biology, HPV testing, vaccination, and treatment of HPV-related cancers.
LncRNA SNHG8 accelerates proliferation and inhibits apoptosis in HPV-induced cervical cancer through recruiting EZH2 to epigenetically silence RECK expression.
Qu Xiaohui,Li Yuanyuan,Wang Lin,Yuan Ningxia,Ma Meng,Chen Yao
Journal of cellular biochemistry
Infection of human papillomaviruses (HPVs), such as subtypes HPV16 and HPV18 is carcinogenic to human and is prominent cause of HPV-positive cervical carcinoma (CC). A closer investigation into the mechanism of HPV-induced CC may stimulate the generation of an improved therapy treating cervical cancer. Our study herein interrogated the function of a small nucleolar RNA host gene 8 (SNHG8) in HPV-induced CC. As a result, a notable increase of SNHG8 in HPV-induced CC cells was found compared with HPV-negative CC cells. Functionally, it identified that SNHG8 aggravated the cell proliferation and migration in Cell Counting Kit-8 and transwell assays. Besides, flow cytometry apoptosis assay displayed that blockade of SNHG8 exacerbated apoptosis of HPV-positive CC cells. As detected by fluorescence in situ hybridization analysis and subcellular fractionation assay, SNHG8 was primarily expressed in the nucleus and exerted suppressive role on reversion inducing cysteine-rich protein with kazal motifs (RECK) expression, which implied a potential transcriptional regulation of SNHG8 on RECK level. Mechanically, SNHG8 was disclosed to interact with enhancer of zeste homolog 2 (EZH2) based on RNA immunoprecipitation assay. ChIP assay further unveiled the occupancy of EZH2 in the promoter region of RECK. An additional chromatin immunoprecipitation assay highlighted that SNHG8 intensified the enrichment of EZH2 and H3K27me3 in RECK promoter region. Altogether, it reflected that SNHG8 recruited EZH2 to downregulate RECK expression, leading to HPV-induced CC aggravation.
Profiling HPV-16-specific T cell responses reveals broad antigen reactivities in oropharyngeal cancer patients.
Bhatt Kunal H,Neller Michelle A,Srihari Sriganesh,Crooks Pauline,Lekieffre Lea,Aftab Blake T,Liu Howard,Smith Corey,Kenny Liz,Porceddu Sandro,Khanna Rajiv
The Journal of experimental medicine
Cellular immunotherapeutics targeting the human papillomavirus (HPV)-16 E6 and E7 proteins have achieved limited success in HPV-positive oropharyngeal cancer (OPC). Here we have conducted proteome-wide profiling of HPV-16-specific T cell responses in a cohort of 66 patients with HPV-associated OPC and 22 healthy individuals. Unexpectedly, HPV-specific T cell responses from OPC patients were not constrained to the E6 and E7 antigens; they also recognized E1, E2, E4, E5, and L1 proteins as dominant targets for virus-specific CD8+ and CD4+ T cells. Multivariate analysis incorporating tumor staging, treatment status, and smoking history revealed that treatment status had the most significant impact on HPV-specific CD8+ and CD4+ T cell immunity. Specifically, the breadth and overall strength of HPV-specific T cell responses were significantly higher before the commencement of curative therapy than after therapy. These data provide the first glimpse of the overall human T cell response to HPV in a clinical setting and offer groundbreaking insight into future development of cellular immunotherapies for HPV-associated OPC patients.
Cervicovaginal microbiome and natural history of HPV in a longitudinal study.
Usyk Mykhaylo,Zolnik Christine P,Castle Philip E,Porras Carolina,Herrero Rolando,Gradissimo Ana,Gonzalez Paula,Safaeian Mahboobeh,Schiffman Mark,Burk Robert D,
BACKGROUND:Human papillomavirus (HPV) infection is one of the most common sexually transmitted infections. However, only a small percentage of high-risk (HR) HPV infections progress to cervical precancer and cancer. In this study, we investigated the role of the cervicovaginal microbiome (CVM) in the natural history of HR-HPV. METHODS:This study was nested within the placebo arm of the Costa Rica HPV Vaccine Trial that included women aged 18-25 years of age. Cervical samples from two visits of women with an incident HR-HPV infection (n = 273 women) were used to evaluate the prospective role of the CVM on the natural history of HR-HPV. We focus specifically on infection clearance, persistence, and progression to cervical intraepithelial neoplasia grade 2 and 3 (CIN2+). The CVM was characterized by amplification and sequencing the bacterial 16S V4 rRNA gene region and the fungal ITS1 region using an Illumina MiSeq platform. OTU clustering was performed using QIIME2. Functional groups were imputed using PICRUSt and statistical analyses were performed using R. RESULTS:At Visit 1 (V1) abundance of Lactobacillus iners was associated with clearance of incident HR-HPV infections (Linear Discriminant Analysis (LDA)>4.0), whereas V1 Gardnerella was the dominant biomarker for HR-HPV progression (LDA>4.0). At visit 2 (V2), increased microbial Shannon diversity was significantly associated with progression to CIN2+ (p = 0.027). Multivariate mediation analysis revealed that the positive association of V1 Gardnerella with CIN2+ progression was due to the increased cervicovaginal diversity at V2 (p = 0.040). A full multivariate model of key components of the CVM showed significant protective effects via V1 genus Lactobacillus, OR = 0.41 (0.22-0.79), V1 fungal diversity, OR = 0.90 (0.82-1.00) and V1 functional Cell Motility pathway, OR = 0.75 (0.62-0.92), whereas V2 bacterial diversity, OR = 1.19 (1.03-1.38) was shown to be predictive of progression to CIN2+. CONCLUSION:This study demonstrates that features of the cervicovaginal microbiome are associated with HR-HPV progression in a prospective longitudinal cohort. The analyses indicated that the association of Gardnerella and progression to CIN2+ may actually be mediated by subsequent elevation of microbial diversity. Identified features of the microbiome associated with HR-HPV progression may be targets for therapeutic manipulation to prevent CIN2+. TRIAL REGISTRATION:ClinicalTrials.gov NCT00128661.