HPV E7 affects the function of cervical cancer cells via the TAL1/lnc-EBIC/KLHDC7B axis

Abstract

High-risk human papillomavirus (HPV)16 and 18 are the primary cause of cervical cancer (CC) and long non-coding RNAs (lncRNAs/lncs) are often abnormally expressed in patients with CC. The authors' previous study indicated that oncogenic enhancer of zeste homolog 2 (EZH2)-binding lncRNA in cervical cancer (lnc-EBIC) serves a role in the tumorigenic activity of the HPV E6 protein in patients with CC. However, whether HPV E7 affects the devel- opment of CC through lnc-EBIC, and the potential mechanisms underlying this remains unclear. Therefore, the present study investigated the effects of lnc-EBIC and HPV E7 in cervical cancer cell lines HeLa, CaSki and C33A in vitro. CCK-8, EdU and DAPI staining assays, flow cytometry, RT-qPCR, western blotting and Transwell assay were performed on these cell lines. The results revealed that exogenous expression of HPV16/18 E7 significantly promoted lnc-EBIC expression, and conversely, lnc-EBIC was downregulated by silencing endogenous HPV16/18 E7 expression in corresponding CaSki and HeLa cells. Overexpression of lnc-EBIC significantly increased cellular proliferation, migration and invasion, and inhibited apoptosis in HPV- C33A cells. The tumorigenic effects of HPV16/18 E7 in corresponding CaSki and HeLa cells were significantly blocked by the silencing of lnc-EBIC expression. Molecular analysis revealed that HPV16/18 E7 depended on TAL BHLH transcription factor 1, erythroid differentiation factor inhibition to promote lnc-EBIC expression, which also resulted in the upregulation of oncogenic Kelch domain-containing 7B (KLHDC7B) in corresponding CaSki and HeLa cells. Additionally, KLHDC7B knockdown blocked the tumor-promotive effects of lnc-EBIC in HPVC33A cells. Collectively, the results of the present study indicated that lnc-EBIC acts as an oncogenic lncRNA by enhancing KLHDC7B expression in HPV+ and HPV. CC cells, and can be exploited by HPV16/18 E7 to accelerate tumorigenic activity in CC. These results further revealed that the lnc-EBIC/KLHDC7B axis represents a novel molecular mechanism and potential therapeutic target for CC.