环状RNA hsa_circ_0002717/miRNA/TCF4环路调控自噬促进HSC活化

Hepatic stellate cell (HSC) activation is a central mechanism underlying liver fibrogenesis. Autophagy functions as an important driver of HSC activation and hepatic fibrosis. However, it is not well know that whether circular RNA(circRNA) plays an important role in the autophagy and activated of HSC. In our recent study, hsa_circ_0002717 was observed in the fibrotic liver tissues from patients or experimental rats as well as in activated HSC. The computational algorithm analysis and luciferase reporter assay revealed that hsa_circ_0002717 could sponge both of miR-155 and miR-203a-3p to regulate their common target gene TCF4. In this study, we will further focus on the role of hsa_circ_0002717/miRNA/TCF4 circuit in HSC autophagy and activation. First of all, the association of differential expression of hsa_circ_0002717 with HSC activation and hepatic fibrogenesis will be confirmed. Sencond, hsa_circ_0002717 will be changed in HSC to comfirm the effect of this circRNA on its direct target miRNA, as well as on TCF4 expression and HSC autophagy, which might lead to the activation of HSC and hepatic fibrosis. Then we will demonstrate the crosstalk between hsa_circ_0002717, miR-155, miR-203a-3p, and TCF4 , confirm the molecular mechanism of hsa_circ_0002717/miRNA/TCF4 circuit in HSC activation. Finally, the inhibitory effect of hsa_circ_0002717 on hepatic fibrosis will be investigated in vivo, which may represent a promising novel therapeutic method for hepatic fibrosis.

HSC活化是肝纤维化发展的重要环节，HSC自噬可促进其活化，目前尚无环状RNA（circRNA）调控HSC自噬及活化的相关研究。前期工作发现，hsa_circ_0002717在纤维化肝脏组织及活化HSC中明显上调，它可能和miR-155、miR-203a-3p及该miRNAs共同靶基因TCF4形成环路促进HSC自噬及活化。本课题进一步证实hsa_circ_0002717差异表达与肝纤维化的相关性；双向调控HSC hsa_circ_0002717表达，研究其对miRNAs的竞争抑制及对TCF4的影响，观察其对HSC自噬、活化及肝纤维化的影响；阐明hsa_circ_0002717与miRNAs及TCF4的“crosstalk”关系，明确环状RNA/miRNA/TCF4环路调控自噬促进HSC活化的分子机制；探讨下调hsa_circ_0002717表达的抗纤维化作用，为治疗提供新的靶点。

HSC活化是肝纤维化发展的重要环节，HSC自噬可促进其活化，目前尚无环状RNA（circRNA）调控HSC自噬及活化的相关研究。前期工作发现，hsa_circ_0002717在纤维化肝脏组织及活化HSC中明显上调，它可能和miR-155、miR-203a-3p及该miRNAs共同靶基因TCF4形成环路促进HSC自噬及活化。本课题进一步证实hsa_circ_0002717差异表达与肝纤维化的相关性；双向调控HSC hsa_circ_0002717表达，研究其对miRNAs的竞争抑制及对TCF4的影响，观察其对HSC自噬、活化及肝纤维化的影响；阐明hsa_circ_0002717与miRNAs及TCF4的“crosstalk”关系，明确环状RNA/miRNA/TCF4环路调控自噬促进HSC活化的分子机制；探讨下调hsa_circ_0002717表达的抗纤维化作用，为治疗提供新的靶点。