The high-risk HPV oncogene E7 upregulates miR-182 expression through the TGF-β/Smad pathway in cervical cancer

Accumulating experimental evidence has shown that the aberrant expression of microRNAs (miRNAs) is involved in the development and progression of human cervical cancer. Previously, we identified miR-182 as an oncomiRNA in cervical cancer. However, the mechanism by which miR-182 is regulated and the interaction between human papillomavirus (HPV) and miR-182 in cervical cancer development remains unknown. In the present study, we explored the link between HPV E7 and miR-182 and verified that high-risk HPV E7 upregulated miR-182 expression through TGF-beta/Smad4 signaling pathway in cervical cancer. By contrast, low-risk HPV E7 did not affect the expression of TGF-beta and miR-182. Mechanistically, as high-risk HPV E7 bound to pRb, E2F was released from the complex and bound to the TGF-beta promoter region, resulting in TGF-beta overexpression. Furthermore, the Smad4 signaling pathway was activated upon TGF-beta overexpression, which led to an interaction between Smad4 and the miR-182 promoter region, subsequently inducing the upregulation of miR-182 in both cervical cancer cells and the surrounding normal cells. In conclusion, this newly identified high-risk HPV E7/TGF-beta/miR-182 regulatory network might inform the development of specific therapeutic strategies for cervical cancer.