The E6-TAp63β-Dicer feedback loop involves in miR-375 downregulation and epithelial-to-mesenchymal transition in HR-HPV+ cervical cancer cells

MiR-375 has been recognized as an important tumor suppressor and is usually downregulated in cervical cancer. However, how it is downregulated in cervical cancer is not clear. By using cancerous and normal cervical tissues, we observed that miR-375 and Dicer are both downregulated and were positively correlated. Overexpression of miR-375 resulted in decreased viral E6 and increased Dicer expression in both Hela and SiHa cells. Previous studies suggest that E6 can induce an accelerated degradation of TAp63β, while TAp63 can bind to and transactivate the Dicer promoter, exerting a direct regulation on transcription of Dicer. In this study, we found that miR-375 overexpression restored TAp63β expression. TAp63β overexpression significantly enhanced transcription and translation of Dicer, which further led to increased mature miR-375 levels. Therefore, we infer that there is an E6-TAp63β-Dicer feedback loop involved in miR-375 dysregulation in cervical cancer. Besides, we observed that enforced TAp63β expression significantly reduced the mesenchymal markers including N-cadherin, Vimentin, Snail, and Slug but increased the epithelial marker E-cadherin in both Hela and SiHa cells. The wound healing assay also confirmed that TAp63β overexpression significantly suppressed cervical cancer cell migration potential. These results suggest that TAp63β can inhibit epithelial-to-mesenchymal transition (EMT) of cervical cancer cells.