TRAF2 decrease promotes the TGF-β-mTORC1 signal in MAFLD-HCC through enhancing AXIN1-mediated Smad7 degradation

According to recent research, metabolic-associated fatty liver disease (MAFLD) has emerged as an important underlying etiology of hepatocellular carcinoma (HCC). However, the molecular mechanism of MAFLD-HCC is still unclear. Tumor necrosis factor receptor-associated factor 2 (TRAF2) is the key molecule to mediate the signal of inflammatory NF-kappa B pathway. This study aims to investigate the potential dysregulation of TRAF2 and its biological function in MAFLD-HCC. Huh7 TRAF2(-/-) demonstrated increased tumor formation ability compared to huh7 TRAF2(+/+) when stimulated with transforming growth factor-beta (TGF-beta). The decisive role of TGF-beta in the development of MAFLD-HCC was confirmed through the specific depletion of TGF-beta receptor II gene in the hepatocytes (Tgfbr2 Delta Hep) of mice. In TRAF2(-/-) cells treated with TGF-beta, both the glycolysis rate and lipid synthesis were enhanced. We proved the signal of the mechanistic target of rapamycin complex 1 (mTORC1) could be activated in the presence of TGF-beta, and was enhanced in TRAF2(-/-) cells. The coimmunoprecipitation (co-IP) experiments revealed that TRAF2 fortified the Smurf2-mediated ubiquitination degradation of AXIN1. Hence, TRAF2 depletion resulted in increased Smad7 degradation induced by AXIN1, thus promoting the TGF-beta signal. We also discovered that PLX-4720 could bind with AXIN1 and restrained the tumor proliferation of TRAF2(-/-) in mice fed with high-fat diet (HFD). Our findings indicate that TRAF2 plays a significant role in the pathogenesis of MAFLD-HCC. The reduction of TRAF2 expression leads to the enhancement of the TGF-beta-mTORC1 pathway by facilitating AXIN1-mediated Smad7 degradation.