Understanding the HPV integration and its progression to cervical cancer

Oyervides-Muñoz, Mariel Araceli; Pérez-Maya, Antonio Alí; Rodríguez-Gutiérrez, Hazyadee Frecia; Gómez‐Macías, Gabriela Sofía; Fajardo-Ramírez, Óscar R; Treviño, Víctor; Barrera-Saldaña, Hugo A.; Garza‐Rodríguez, María Lourdes

doi:10.1016/j.meegid.2018.03.003

Cited by 124 publications

(117 citation statements)

References 74 publications

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“…The HPV16 physical state is in episomal, integrated, and mixed forms in cervical lesions. The integration of HPV DNA can lead to a series of host responses, dysregulated expression of E6 and E7 , disrupted tumor suppressor genes and increased genetic instability …”

Section: Introductionmentioning

confidence: 99%

Genetic variability and functional implication of HPV16 from cervical intraepithelial neoplasia in Shanghai women

Zhao

Zhu

Guo

et al. 2019

Journal of Medical Virology

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Human papillomavirus (HPV)16 gene mutation is usually associated with persistent HPV infection and cervical intraepithelial neoplasia (CIN). However, the functional implications of HPV16 mutations remain poorly understood.145 LCR/E6/E7 of the HPV16 isolates were amplified and sequenced, and HPV16 integration status was detected. In total, 89 SNPs (68 in the LCR, 13 in E6, 8 in E7) were discovered, 11 of which were nonsynonymous mutations (8 in E6, 3 in E7). The H85Y and E120D variants in E6 were significantly reduced in the high-grade squamous intraepithelial lesion (HSIL) group compared to the T," a potential binding site for TATA-binding protein, is the most common in LCR variants. A4 (Asian) was associated with an increased risk of HSIL compared to A1-3(P = .009). The H85/E120 in E6 and N29 in HPV16 E7 might play a critical role in carcinogenesis by disrupting p53 and Rb degradation due to affecting their interaction, respectively. In a word, the findings in this study provide preventative and therapeutic interventions of HPV16 -related cervical lesions/cancer.

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Section: Introductionmentioning

confidence: 99%

Genetic variability and functional implication of HPV16 from cervical intraepithelial neoplasia in Shanghai women

Zhao

Zhu

Guo

et al. 2019

Journal of Medical Virology

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“…Although persistent infection with HPV 16/18 is regarded as the most important cofactor for CC progression [2,3], it is insu cient on its own. Emerging evidence has indicated that the TME is a critical contributor to cancer progression [6][7][8][9][10].…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicular Wnt7b mediates HPV E6-induced cervical cancer angiogenesis by activating the β-catenin signaling pathway

Qiu

Sun

Tang

et al. 2020

Preprint

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Background: The E6 oncoproteins of human papillomavirus (HPV) 16/18 are the critical drivers of cervical cancer (CC) progression. Extracellular vesicles (EVs) are emerging as critical mediators of cancer-tumor microenvironment (TME) communication. However, whether EVs contribute to HPV 16/18 E6-mediated impacts on CC progression remains unclear. Methods: A series of in vitro and in vivo assays were performed to elucidate the roles and mechanism of EV-Wnt7b in HPV E6-induced CC angiogenesis. The prognostic value of serum EV-Wnt7b was determined and a predictive nomogram model was established. Results: HPV 16/18 E6 upregulated Wnt7b mRNA expression in four HPV 16/18-positive CC cell lines and their EVs. In vitro and in vivo experiments demonstrated that EV-Wnt7b mRNA was transferred to and modulated human umbilical vein endothelial cells (HUVECs) toward more proliferative and proangiogenic behaviors by impacting β-catenin signaling. Clinically, serum EV-Wnt7b levels were elevated in CC patients and significantly correlated with an aggressive phenotype. Serum EV-Wnt7b was determined to be an independent prognostic factor for CC overall survival (OS) and recurrence-free survival (RFS). Notably, we successfully established a novel predictive nomogram model using serum EV-Wnt7b, which showed good prediction of 1- and 3-year OS and RFS. Conclusions: Our results illustrate a potential crosstalk between HPV 16/18-positive CC cells and HUVECs via EVs in the TME and highlight the potential of circulating EV-Wnt7b as a novel predictive biomarker for CC prognosis.

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“…HPVs persistent infection is the causative cause of cervical cancer . Some of the hrHPV persistent infection will be followed by viral DNA integration with human genome, resulting in over expression of two viral oncogene E6 and E7 . These oncoproteins bind to the tumor suppressor genes p53 and the retinoblastoma protein (pRB), destroy their function, leading to dysplasia and invasive cancer .…”

Section: Discussionmentioning

confidence: 99%

“…[32][33][34][35] Some of the hrHPV persistent infection will be followed by viral DNA integration with human genome, resulting in over expression of two viral oncogene E6 and E7. [36][37][38][39][40] These oncoproteins bind to the tumor suppressor genes p53 and the retinoblastoma protein (pRB), destroy their function, leading to dysplasia and invasive cancer. [41][42][43] Therefore, the inhibition of E6 and E7 expression will stop or regress the development of high-grade CIN and thus reduces invasive cancer.…”

Section: Discussionmentioning

confidence: 99%

REBACIN® as a noninvasive clinical intervention for high‐risk human papillomavirus persistent infection

Yang

Duan

et al. 2019

Intl Journal of Cancer

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The development of highly sensitive HPV‐genotyping tests has opened the possibility of treating HPV‐infected women before high‐grade lesions appear. The lack of efficient intervention for persistent high‐risk HPV infection necessitates the need for development of novel therapeutic strategy. Here we demonstrate that REBACIN®, a proprietary antiviral biologics, has shown potent efficacy in the clearance of persistent HPV infections. Two independent parallel clinical studies were investigated, which a total of 199 patients were enrolled and randomly divided into a REBACIN®‐test group and a control group without treatment. The viral clearance rates for the REBACIN® groups were 61.5% (24/39) and 62.5% (35/56), respectively, for the two independent parallel studies. In contrast, the nontreatment groups showed self‐clearance rates at 20.0% (8/40) and 12.5% (8/64). We further found that REBACIN® was able to significantly repress the expression of HPV E6 and E7 oncogenes in TC‐1 and Hela cells. The two viral genes are well known for the development of high‐grade premalignancy lesion and cervical cancer. In a mouse model, REBACIN® was indicated to notably suppress E6/E7‐induced tumor growth, suggesting E6 and E7 oncogenes as a potential target of REBACIN®. Taken together, our studies shed light into the development of a novel noninvasive therapeutic intervention for clearance of persistent HPV infection with significant efficacy.

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Understanding the HPV integration and its progression to cervical cancer

Cited by 124 publications

References 74 publications

Genetic variability and functional implication of HPV16 from cervical intraepithelial neoplasia in Shanghai women

Genetic variability and functional implication of HPV16 from cervical intraepithelial neoplasia in Shanghai women

Extracellular vesicular Wnt7b mediates HPV E6-induced cervical cancer angiogenesis by activating the β-catenin signaling pathway

REBACIN® as a noninvasive clinical intervention for high‐risk human papillomavirus persistent infection

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