Circ-DENND4C Up-regulates TCF4 Expression to Modulate Hepatocellular Carcinoma Cell Proliferation and Apoptosis Via Activating Wnt/β-catenin Signal Pathway

Background: Hepatocellular carcinoma (HCC) is a common malignant tumor in China. Advanced treatment like transcatheter hepatic arterial chemoembolization (TACE) has prolonged the lives of many HCC patients. However, the prognosis of most HCC patients remains unsatisfactory. Recently, circular RNAs (circRNAs) have been gradually unveiled to exert considerable functions in cancer. Promising circRNAs in HCC remains to be further elucidated.

Methods: Gene expression was assessed by qRT-PCR and western blot. The function of circ-DENND4C in HCC was estimated by both in vitro and in vivo experiments. The location of circ-DENND4C in HCC cells was determined by subcellular fractionation and FISH assays. The association among molecules were analyzed through RNA pull down, RIP and luciferase reporter assays.

Results: circ-DENND4C (DENN domain containing 4C), an oncogene identified in breast cancer, was overexpressed in HCC cells. Also, circ-DENND4C exerted pro-tumor functions in HCC through activating Wnt/β-catenin pathway. Importantly, circ-DENND4C could augment transcription factor 4 (TCF4) expression to activate Wnt/β-catenin signaling via sequestering miR-195-5p. Moreover, following rescue assays disclosed that circ-DENND4C mediated malignant phenotypes in HCC cells via up-regulating TCF4 through sponging miR-195-5p.

Conclusion: circ-DENND4C boosted TCF4 expression to modulate malignant behaviors of HCC cells via activating Wnt/β-catenin pathway, which might offer a promising target for HCC treatment.