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

Area of Science:

• Hepatology and Cancer Biology
• Molecular Mechanisms of Liver Disease
• Oncogenesis

Background:

• Metabolic-associated fatty liver disease (MAFLD) is a growing cause of hepatocellular carcinoma (HCC).
• The precise molecular pathways linking MAFLD to HCC remain incompletely understood.
• Tumor necrosis factor receptor-associated factor 2 (TRAF2) is implicated in inflammatory signaling pathways relevant to cancer.

Purpose of the Study:

• To investigate the role and molecular function of TRAF2 in the pathogenesis of MAFLD-associated HCC.
• To elucidate the signaling pathways influenced by TRAF2 dysregulation in MAFLD-HCC.

Main Methods:

• Utilized TRAF2 knockout (TRAF2^-/-) and wild-type (TRAF2^+/+) Huh7 cells and Tgfbr2ΔHep mice.
• Stimulated cells with transforming growth factor-β (TGF-β) and analyzed glycolysis and lipid synthesis.
• Employed co-immunoprecipitation (co-IP) to study protein interactions and degradation pathways.
• Administered PLX-4720 to TRAF2^-/- mice on a high-fat diet (HFD).

Main Results:

• TRAF2^-/- cells exhibited enhanced tumor formation upon TGF-β stimulation.
• TGF-β signaling was confirmed as critical in MAFLD-HCC development.
• TRAF2 deficiency led to increased glycolysis, lipid synthesis, and mechanistic target of rapamycin complex 1 (mTORC1) activation under TGF-β influence.
• TRAF2 loss promoted AXIN1-mediated degradation of Smad7, thereby enhancing TGF-β signaling.
• PLX-4720 treatment inhibited tumor proliferation in TRAF2^-/- mice on HFD.

Conclusions:

• TRAF2 plays a crucial protective role in MAFLD-HCC.
• Reduced TRAF2 expression exacerbates MAFLD-HCC by activating the TGF-β-mTORC1 pathway via enhanced AXIN1-mediated Smad7 degradation.
• Targeting AXIN1 with agents like PLX-4720 may offer therapeutic strategies for MAFLD-HCC.