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High-Risk Human Papillomavirus E7 Maintains Stemness Via APH1B In Cervical Cancer Stem-Cell Like Cells

Authors Yang S, Chen T, Huang L, Xu S, Cao Z, Zhang S, Xu J, Li Y, Yue Y, Lu W, Cheng X, Xie X

Received 19 November 2018

Accepted for publication 30 September 2019

Published 12 November 2019 Volume 2019:11 Pages 9541—9552

DOI https://doi.org/10.2147/CMAR.S194239

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Andrew Yee

Peer reviewer comments 2

Editor who approved publication: Dr Rituraj Purohit


Shizhou Yang,1,* Tingting Chen,1,* Lu Huang,2 Shanshan Xu,1 Zhu Cao,1 Songfa Zhang,1 Junfen Xu,1 Yang Li,1 Yongfang Yue,1 Weiguo Lu,1,3 Xiaodong Cheng,1,3 Xing Xie1,3

1Department of Gynecologic Oncology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China; 3Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Hangzhou, Zhejiang, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Xing Xie Tel +86 571 8706 1501
Fax +86 571 8706 1878
Email xiex@zju.edu.cn

Purpose: To determine whether early proteins from high-risk human papillomavirus (HPV) have the capacity to maintain cellular stemness.
Patients and methods: First, we isolated cancer stem cell like cells from two cervical cancer cell lines, SiHa and CaSki, using non-adhesive culture with serum-free medium. Second, we knocked down HPV16 E7 in SiHa sphere cells and overexpressed HPV16 E7 in U2OS sphere cells. Third, we used RNA-seq analysis and Western blotting to screen and identify the expression of differentially expressed genes in SiHa cells with HPV16 E7 knockdown.
Results: We found that both SiHa and CaSki cells grew as cell spheres (oncospheres) and shared the properties of cancer stem cells, including high expression of stem cell marker OCT4 and SOX2, self-renew, and resistance to chemotherapeutic drugs. The stem-like properties were deprived when HPV16 E7 was knocked down in SiHa sphere cells and maintained when HPV16 E7 was over-expressed in U2OS sphere cells. APH1B was up-regulated, among differential expression genes, in SiHa cells with HPV16 E7 knockdown and modulated cellular stemness and SiHa sphere cells with APH1B knockdown regained the stem-like properties deprived by E7 inhibition.
Conclusion: HPV16 E7 possesses the capacity to maintain cellular stemness and APH1B may participate in this process in cervical cancer sphere cells.

Keywords: cervical cancer, HPV, cancer stem cell, APH1B

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