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Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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TRAF2 decrease promotes the TGF-β-mTORC1 signal in MAFLD-HCC through enhancing AXIN1-mediated Smad7 degradation.

Zhonglin Li1, Jinfang Zhao1, Ya Wu2

  • 1Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|February 16, 2024
PubMed
Summary

Tumor necrosis factor receptor-associated factor 2 (TRAF2) deficiency promotes metabolic-associated fatty liver disease (MAFLD) and hepatocellular carcinoma (HCC) by enhancing the TGF-β-mTORC1 pathway. TRAF2 reduction accelerates tumor growth in MAFLD-HCC.

Keywords:
AXIN1MAFLDTGF-βTRAF2hepatomamTORC1

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Mechanistic Insight into the Development of TNBS-Mediated Intestinal Fibrosis and Evaluating the Inhibitory Effects of Rapamycin
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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.