m6A modification of circHPS5 and hepatocellular carcinoma progression through HMGA2 expression

Dawei Rong; Fan Wu; Chen Lu; Guangshun Sun; Xiaoli Shi; Xiaoyuan Chen; Yongjiu Dai; Weizhe Zhong; Xiaopei Hao; Jinren Zhou; Yongxiang Xia; Weiwei Tang; Xuehao Wang

doi:10.1016/j.omtn.2021.09.001

m6A modification of circHPS5 and hepatocellular carcinoma progression through HMGA2 expression

Mol Ther Nucleic Acids. 2021 Sep 14:26:637-648. doi: 10.1016/j.omtn.2021.09.001. eCollection 2021 Dec 3.

Authors

Dawei Rong^{1

2}, Fan Wu³, Chen Lu⁴, Guangshun Sun³, Xiaoli Shi^{1

2}, Xiaoyuan Chen^{1

2}, Yongjiu Dai¹, Weizhe Zhong¹, Xiaopei Hao¹, Jinren Zhou¹, Yongxiang Xia¹, Weiwei Tang¹, Xuehao Wang¹

Affiliations

¹ Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China.
² School of Medicine, Southeast University, Nanjing, Jiangsu, China.
³ Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
⁴ Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.

Abstract

N6-methyladenosine (m6A) is capable of mediating circRNA generation in carcinoma biology. Nevertheless, the posttranscriptional systems of m6A and circRNA in hepatocellular carcinoma (HCC) development are still unclear. The present study identified a circRNA with m6A modification, circHPS5, which was increased in neoplasm HCC tissues and indicated poor patient survival. Silencing of circHPS5 inhibited epithelial-mesenchymal transition (EMT) and cancer stem-like cell (CSC) phenotypes. Notably, METTL3 could direct the formation of circHPS5, and specific m6A controlled the accumulation of circHPS5. YTHDC1 facilitated the cytoplasmic output of circHPS5 under m6A modification. In addition, we demonstrated that circHPS5 can act as a miR-370 sponge to regulate the expression of HMGA2 and further accelerate HCC cell tumorigenesis. Accordingly, the m6A modification of circHPS5 was found to modulate cytoplasmic output and increase HMGA2 expression to facilitate HCC development. The new regulatory model of "circHPS5-HMGA2" provides a new perspective for circHPS5 as an important prognostic marker and therapeutic target in HCC and provides mechanistic insight for exploring the carcinogenic mechanism of circHPS5 in HCC.

Keywords: HMGA2; circHPS5; circRNA; epithelial-mesenchymal transition; hepatocellular carcinoma; m6A modification.