High-Risk Human Papillomavirus E7 Maintains Sternness Via APHIB In Cervical Cancer Stem-Cell Like Cells

Purpose: To determine whether early proteins from high-risk human papillomavirus (HPV) have the capacity to maintain cellular sternness. 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 U20S 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 U20S sphere cells. APHIB was up-regulated, among differential expression genes, in SiHa cells with HPV16 E7 knockdown and modulated cellular sternness and SiHa sphere cells with APHIB knockdown regained the stem-like properties deprived by E7 inhibition. Conclusion: HPV16 E7 possesses the capacity to maintain cellular sternness and APHIB may participate in this process in cervical cancer sphere cells. Keywords: cervical cancer, HPV, cancer stem cell, APHIB