Human papillomavirus E6-regulated microRNA-20b promotes invasion in cervical cancer by targeting tissue inhibitor of metalloproteinase 2.

Abstract

Human papillomavirus (HPV) infection alone is not sufficient for development of cervical cancer and further risk factors are involved, however, the underlying mechanism remains to be elucidated. The authors previously used a microarray assay to reveal microR-20b (miR-20b) as a key node in the miRNA-mRNA network of cervical carcinoma. The present study demonstrated an increased expression of miR-20b in cervical carcinoma tissue. MiR-20b was regulated by HPV E6 oncoprotein in cervical cancer. Furthermore, miR-20b overexpression with mimics induced cell morphological alterations and the epithelial-mesenchymal transition. Treating cervical cancer cells with the miR-20b inhibitor decreased the migration and invasion of cervical cancer cells. Tissue inhibitor of metalloproteinase 2 (TIMP-2), a possible antagonist of matrix metalloproteinase 2, is a metastasis suppressor and predicted to be a potential target of miR-20b. Fluorescence signals were decreased on transducing HeLa cells with a TIMP-2 3′-untranslated region plasmid and miR-20b mimics compared with control. Finally, TIMP-2 was identified as a novel target of miR-20b and was demonstrated to be regulated by the HPV oncoprotein. In addition, miR-20b and TIMP-2 were involved in cell invasion regulated by HPV E6. The present study demonstrated a novel pathway of HPV/miR-20b/TIMP-2 during the process of invasion in cervical cancer cells.