Circ_0007386 Promotes the Progression of Hepatocellular Carcinoma Through the miR-507/ CCNT2 Axis

Yanzhi Feng,1– 4,* Litao Liang,1– 4,* Wenbo Jia,1– 4 Jinyi Wang,1– 4 Chao Xu,1– 4 Deming Zhu,1– 4 Bin Xu,1– 4 Wenhu Zhao,1– 4 Xiangyu Ling,1– 4 Yongping Zhou,5 Lianbao Kong,1– 4,* Wenzhou Ding1– 4,* 1Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, People’s Republic of China; 3Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, People’s Republic of China; 4Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, People’s Republic of China; 5Jiangnan University Medical Center, JUMC, Department of Hepatobiliary, Wuxi, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenzhou Ding; Lianbao Kong, Hepatobiliary Centre, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People’s Republic of China, Email dingwenzhou@njmu.edu.cn; lbkong@njmu.edu.cnBackground: Circular RNAs (circRNAs) have been shown to play a crucial role in the initiation and development of Hepatocellular carcinoma (HCC). However, the mechanism and function of circ_0007386 in HCC are still unknown.Methods: Circ_0007386 expression level in HCC tissues, and HCC cell lines was further analyzed by qRT-PCR. Agarose gel electrophoresis and Sanger sequencing were used to figure out the structure of circ_0007386. The involvement of circ_0007386 in HCC development was evaluated by experimental investigations conducted in both laboratory settings (in vitro) and living organisms (in vivo). RNA immunoprecipitation, Western blotting, luciferase reporter assay and fluorescence in situ hybridization (FISH) were applied for finding out the interaction among circ_0007386, miR-507 and CCNT2. To assess the connection between circ_0007386 and lenvatinib resistance, lenvatinib-resistant HCC cell lines were employed.Results: The expression of circ_0007386 was found to increase in HCC tissues, and it was observed to be associated with a worse prognosis. Overexpression of circ_0007386 stimulated HCC cells proliferation, invasion, migration and the epithelial–mesenchymal transition (EMT) while silencing of circ_0007386 resulted in the opposite effect. Mechanistic investigations revealed that circ_0007386 acted as a competing endogenous RNA of miR-507 to prevent CCNT2 downregulation. Downregulating miR-507 or overexpressing CCNT2 could reverse phenotypic alterations that originated from inhibiting of circ_0007386. Importantly, circ_0007386 determines the resistance of hepatoma cells to lenvatinib treatment.Conclusion: Circ_0007386 advanced HCC progression and lenvatinib resistance through the miR-507/ CCNT2 axis. Meanwhile, circ_0007386 served as a potential biomarker and therapeutic target in HCC patients. Keywords: hepatocellular carcinoma, circ_0007386, miR-507, CCNT2, Lenvatinib