CREB1 acts via the miR-922/ARID2 axis to enhance malignant behavior of liver cancer cells

Abstract

There is little information on the role of microRNA (miR)-922 in the malignant behavior of liver cancer. The present study investigated the regulation of miR-922 expres- sion levels by cAMP response element binding protein 1 (CREB1) in liver cancer tissue, its role in regulating malignant behavior and its potential targets in liver cancer. miR-922 expression in liver cancer cells and tissue was determined by reverse transcription-quantitative PCR. The binding of CREB1 to the promoter region of mir-922 was tested by chromatin immunoprecipitation-PCR. The predicted AT-rich interactive domain 2 (ARID2) and fidgetin, microtubule severing factor targets of miR-922 were characterized by dual luciferase reporter assay. The effects of altered ARID2 expression levels on miR-922-enhanced malignant behavior of liver cancer cells were tested. CREB1 bound to the promoter region of miR-922. Elevated miR-922 transcripts were inversely associ- ated with ARID2 expression in liver cancer tissue and cells. miR-922 inhibited ARID2-regulated luciferase expression and was present in the miR/argonaute RISC catalytic compo- nent 2 complex. ARID2 significantly decreased malignant behavior of liver cancer MHCC97L cells. Similarly, ARID2 over-expression inhibited growth of xenograft liver cancer tumors and decreased miR-922, Bcl-2, proliferating cell nuclear antigen, cyclin D1, MMP3 and MMP9 expression and serum VEGF and TNF-α levels, but enhanced Bax expression levels in tumors. ARID2 over-expression abrogated malignant behavior promoted by miR-922 over-expression and enhanced miR-922-decreased malignant behavior of liver cancer cells. CREB induced miR-922 transcription, which targeted ARID2 to enhance malignant behavior of liver cancer cells, indicating that the CREB1/miR-922/ARID2 axis may be a potential target for liver cancer treatment.