RNA-binding protein AUF1 suppresses miR-122 biogenesis by down-regulating Dicer1 in hepatocellular carcinoma

// Xia Wu 1, 3 , Yingzhuo Yang 3 , Yike Huang 1, 2 , Yang Chen 1 , Tianying Wang 1 , Shuo Wu 1 , Lei Tong 1 , Yan Wang 1 , Lexun Lin 1 , Meili Hao 2 , Zhao-Hua Zhong 1 , Fengmin Zhang 1 and Wenran Zhao 2 1 Department of Microbiology, Harbin Medical University, Harbin 150081, China 2 Department of Cell Biology, Harbin Medical University, Harbin 150081, China 3 Department of Infectious Diseases, The Second Affiliated Hospital, Harbin Medical University, Harbin 150081, China Correspondence to: Wenran Zhao, email: zhongwr@hrbmu.edu.cn Fengmin Zhang, email: fengminzhang@ems.hrbmu.edu.cn Zhao-Hua Zhong, email: zhongzh@hrbmu.edu.cn Keywords: AUF1; microRNA biogenesis; miR-122; Dicer1; hepatocellular carcinoma Received: March 31, 2017      Accepted: January 03, 2018      Epub: January 09, 2018      Published: March 13, 2018 ABSTRACT Hepatocellular carcinoma (HCC) is one of the common cancers worldwide, especially in developing countries. Although the chronic infections of hepatitis B and C viruses have been established as the etiological factors of HCC, the mechanism for the tumorigenesis and development of HCC is still unclear. The liver-specific microRNA-122 (miR-122), an established tumor-suppressor miRNA, is often down-regulated in HCC, while the underlying mechanism is not well understood. Here we report that the AU-rich element-binding factor AUF1 suppresses the expression of Dicer1, the type III RNase that is required for microRNA maturation, leading to the inhibited biogenesis of miR-122. Overexpression of AUF1 led to the decreased expression of Dicer1 and miR-122, while the level of the miR-122 precursor (pre-miR-122) was increased. On the other hand, siRNA of AUF1 (siAUF1) increased the levels of Dicer1 mRNA and miR-122, but it reduced the abundance of pre-miR-122. Consistent with the reported data, this study demonstrated that AUF1 and Dicer1 showed opposite expression pattern in both human HCC tissues and cell lines. In addition, AUF1 inhibited the expression of Dicer1 by interacting with the 3′ untranslated region (3′UTR) and coding region of DICER1 mRNA. Moreover, the knockdown of AUF1 by siRNA altered the expression of other miRNAs and promoted HCC cell death. In conclusion, AUF1 down-regulates the expression miR-122 by interacting with the 3′UTR and coding region of DICER1 mRNA and suppressing Dicer1 expression. The AUF1/Dicer1/miR-122 pathway might play a critical role in the development of HCC.