MicroRNA-27b up-regulated by human papillomavirus 16 E7 promotes proliferation and suppresses apoptosis by targeting polo-like kinase2 in cervical cancer

Abstract

The infection with high-risk human papillomavirus is linked to cervical cancer, nevertheless, the role of miRNAs regulated by HPV oncogenes in cancer progression remain largely unknown. Here, we knocked down endogenous E6/E7 in HPV16-positive CaSki cell lines, screened differences in miRNA expression profile with control using miRNA array. 38 miRNAs were down-regulated and 6 miRNAs were up-regulated in the E6/E7 silenced CaSki cells (>2-fold changes with P <0.05). The levels of miR-27b, miR-20a, miR-24, miR-93, and miR-106b were verified by qPCR in E6/E7 silenced CaSki and SiHa cells. MiR-27b, up-regulated by E7, promoted CaSki and SiHa cell proliferation and invasion, inhibit paclitaxel-induced apoptosis. Dual-luciferase experiment confirmed miR-27b down-regulated its target gene PLK2 through the “seed regions”. The tumor suppressor PLK2 inhibited SiHa cell proliferation, reduced cell viability, and promoted paclitaxel/cisplatin -induced apoptosis. Furthermore, DGCR8 was found to mediate the up-regulation of miR-27b by HPV16 E7. Our study demonstrated that HPV16 E7 could increase DGCR8 to promote the generation of miR-27b, which accelerated cell proliferation and inhibited paclitaxel-induced cell apoptosis through down-regulating PLK2. These findings provide an insight into the interaction network of viral oncogene, miR-27b and PLK2, and support the potential strategies using antisense nucleic acid of miR-27b for therapy of cervical cancer in the future.

High Expression of KIF20A Is Associated with Poor Overall Survival and Tumor Progression in Early-Stage Cervical Squamous Cell Carcinoma

“…These E6/E7 oncoproteins have been shown to upregulate A3B (a major mutagenic protein) expression in HPV-induced tumorigenesis [53]. Other proteins, such as KLF13 and DGCR8, have also been implicated in HPV-induced tumorigenesis [54, 55]. In this study, aberrant KIF20A protein expression was observed in HPV-positive cervical cancer samples (31.9%), whereas HPV-negative specimens expressed low levels of KIF20A (16.6%).…”

The human papillomavirus E7 oncoprotein as a regulator of transcription

“…Table 1 shows a summary of these findings, including miRNAs that have been shown to be regulated directly by E7. Other miRNAs have been shown to be regulated by HPV but the specific contribution of E7 (vs. the other viral oncogenes) is not yet known (Martinez, Gardiner et al 2008; Wang, Wang et al 2009; Bonnet, Tatari et al 2010; McKenna, McDade et al 2010; Jung, Phillips et al 2014; Leung, Deng et al 2014; Liu, Gao et al 2014; McKenna, Patel et al 2014; Zheng, Liu et al 2015; Liu, Zhang et al 2016). Only a few of these miRNAs are yet known to have a clear impact on the viral life cycle or on cancer development.…”

Downregulation of microRNA-27b-3p enhances tamoxifen resistance in breast cancer by increasing NR5A2 and CREB1 expression

“…14 Recently, several studies have identified miR-27b-3p (also known as miR-27b) promotes cell proliferation and invasion in glioma and breast cancer, 15, 16 and blocks paclitaxel-induced apoptosis in cervical cancer. 17 MiR-27b-3p also reportedly plays a cancer-promoting role and is associated with poor prognosis in triple-negative breast cancer patients. 17 On the other hand, miR-27b-3p functions as a tumor suppressor to inhibit cells growth, tumor progression and the inflammatory response by inhibiting the expression of PPARγ in neuroblastoma.…”

“…17 MiR-27b-3p also reportedly plays a cancer-promoting role and is associated with poor prognosis in triple-negative breast cancer patients. 17 On the other hand, miR-27b-3p functions as a tumor suppressor to inhibit cells growth, tumor progression and the inflammatory response by inhibiting the expression of PPARγ in neuroblastoma. 18 Moreover, miR-27b-3p attenuates the acquisition of cancer stem cell properties in luminal-type breast cancer by repression of ENPP1.…”