Affiliation:
1. Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University
2. Research Center for Biliary Diseases, West China Hospital, Sichuan University
Abstract
AbstractBackground Our previous study revealed that lnc-TSPAN12 was remarkably upregulated in HCC and correlated with poor survival. However, the role of lnc-TSPAN12 in regulating epithelial-mesenchymal transition (EMT) and metastasis in hepatocellular carcinoma (HCC) remains uncharacterized. Methods The biological function of lnc-TSPAN12 in HCC metastasis was investigated by loss- and gain-of-function experiments both in vitro and in vivo. RNA pull-down, RNA immunoprecipitation and fluorescence in situ hybridisation were performed to examine the interaction between lnc-TSPAN12 and Eukaryotic Translation Initiation Factor 3 subunit I (EIF3I)/Sentrin/SUMO-Specific Protease 1 (SENP1) (SUMO: small ubiquitin-like modifier). EIF3I ubiquitination and SUMOylation modifications were analyzed using co-immunoprecipitation and western blot. Results Functional assays showed that lnc-TSPAN12 positively regulated the migration, invasion and EMT of HCC cells in vitro and accelerated liver metastasis in patient-derived tumour xenograft metastasis models in vivo. Importantly, methyltransferase like 3 (METTL3) mediated N6-methyladenosine modification is responsible for the upregulation of lnc-TSPAN12, contributing to lnc-TSPAN12 stabilization. Mechanistically, lnc-TSPAN12 physically interacts with EIF3I/SENP1 and functions as a scaffold to facilitate the binding of SENP1 to EIF3I, which suppresses EIF3I SUMOylation and ubiquitin degradation, ultimately activating Wnt/β-catenin signalling to promote EMT and metastasis in HCC. Conclusions Our findings elucidate the regulatory mechanism of lnc-TSPAN12 involved in metastasis of HCC and highlight the lnc-TSPAN12-EIF3I/SENP1 axis as a promising therapeutic target for the disease.
Publisher
Research Square Platform LLC