Circular RNA circR-4600 inhibits hepatocellular carcinoma progression by suppressing autophagy through DVL3 and DAB2 interaction

Abstract

Circular RNA (circRNA) plays a crucial role in regulating autophagy in hepatocellular carcinoma (HCC); however, the specific mechanisms underlying this regulation remain poorly understood. This study investigates the role and mechanisms of circR-4600 in HCC, aiming to identify novel therapeutic targets to enhance patient prognosis. Differential expression of circRNA in HCC and adjacent non-tumor tissues from six patients was assessed using circRNA microarray analysis. RNA pulldown combined with ESI-FT-ICR-MS identified DVL3 as the RNA-binding protein that interacts with circR-4600. Functional assays, including overexpression and knockdown experiments in HCC cell lines, as well as in vivo studies, were conducted to evaluate the effects.The results demonstrated significantly lower circR-4600 expression in HCC tissues, which negatively correlated with poor prognosis. Overexpression of circR-4600 inhibited HCC cell proliferation, migration, and invasion in vitro, and reduced lung metastasis in vivo. Mechanistically, circR-4600 interacted with DVL3 to suppress ATG5-mediated autophagy, thereby diminishing DVL3’s inhibitory effect on DAB2, which led to a decreased LC3 II/I ratio and epithelial-mesenchymal transition, while increasing P62 accumulation. In conclusion, circR-4600 modulates autophagy through DVL3 and DAB2, thereby inhibiting HCC progression and providing insights into its potential as a therapeutic target.