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

Abstract

AbstractAccording 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‐κB 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‐β (TGF‐β). The decisive role of TGF‐β in the development of MAFLD‐HCC was confirmed through the specific depletion of TGF‐β receptor II gene in the hepatocytes (Tgfbr2ΔHep) of mice. In TRAF2−/− cells treated with TGF‐β, 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‐β, 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‐β 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‐β‐mTORC1 pathway by facilitating AXIN1‐mediated Smad7 degradation.