Long noncoding RNA Linc01612 represses hepatocellular carcinoma progression by regulating miR-494/ATF3/p53 axis and promoting ubiquitination of YBX1

Pengpeng Liu^1*, Qiu Zhong^1*, Youai Song¹, Deliang Guo¹, Dong Ma¹, Baiyang Chen², Jianwei Lan¹, Quanyan Liu^1,3✉

1. Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, P.R. China.
2. Department of General Surgery, Xiangyang Central Hospital, Affiliated with Hubei University of Arts and Science, Xiangyang, Hubei, P.R. China.
3. Department of Hepatobiliary Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, P.R. China.
*These authors contributed equally to this work.

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Citation:
Liu P, Zhong Q, Song Y, Guo D, Ma D, Chen B, Lan J, Liu Q. Long noncoding RNA Linc01612 represses hepatocellular carcinoma progression by regulating miR-494/ATF3/p53 axis and promoting ubiquitination of YBX1. Int J Biol Sci 2022; 18(7):2932-2948. doi:10.7150/ijbs.69514. Available from https://www.ijbs.com/v18p2932.htm

Abstract

Long noncoding RNAs (lncRNAs) play an important role in the progression of hepatocellular carcinoma (HCC). Linc01612 is a novel lncRNA that function remains unknown in the progression of cancers, including HCC. In this study, we discovered that Linc01612 is significantly down-regulated in HCC tissues than in non-tumor tissues and correlated with poor prognosis. Linc01612 mainly localizes in the cytoplasm and functions as a tumor suppressor by repressing the growth and metastasis of hepatoma cells in vitro and in vivo. Mechanistically, in p53-expressing hepatoma cells, Linc01612 acts as a competitive endogenous RNA and promotes the expression of activation transcription factor 3 (ATF3) by sponging microRNA-494 (miR-494), which in turn inhibits MDM2-mediated ubiquitination of p53 and activates the p53 pathway. Furthermore, in p53-null hepatoma cells, Linc01612 exerts its biological functions by physically interacting with Y-box binding protein 1 protein (YBX1) and promoting the ubiquitin-mediated degradation of YBX1. Interestingly, the Linc01612-YBX1 signaling pathway is also present in p53-expressing hepatoma cells. In conclusion, our study indicated that Linc01612 is a functional lncRNA in HCC and Linc01612 may serve as a potential diagnostic biomarker and therapeutic target for HCC.

Keywords: Hepatocellular carcinoma, Linc01612, ATF3, p53, YBX1