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

Fei Liu,Xinru Mao,Zixian Wu,Qian Wang,Shimeng Zhang,Jinlan Huang,Lei Zheng,Zhen Zhao

doi:10.18632/oncotarget.7531

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.

Highlights

Cervical cancer is one of the most malignant tumors
The infection with high-risk human papillomavirus is linked to cervical cancer, the role of miRNAs regulated by HPV oncogenes in cancer progression remain largely unknown
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

Summary

Introduction

Cervical cancer is one of the most malignant tumors. In 2012, 528,000 new cases of cervical cancer were diagnosed worldwide, of which 266,000 women died [1]. The primary cause of cervical cancer is persistent or chronic infection with one or more of the “high-risk” types of human papillomavirus(HPV) [2]. HPV is the most common sexually transmitted infection. Vaccines to prevent HPV infections are available, WHO recommends routinely administering HPV vaccine to girls 9-13 years of age before sexual activity, as the preventive vaccines do not treat pre-existing HPV infection [1]. For patients with advanced-stage cervical cancer, there is no effective chemotherapy drugs, which make the search for novel therapeutic targets and the development of specific molecular targeting drugs important and urgent

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Conclusion