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Nrf2 induces malignant transformation of hepatic progenitor cells by inducing β-catenin expression

Athanassios Fragoulis1, Julia Schenkel1, Nicole Schröder1

  • 1Department of Anatomy and Cell Biology, Uniklinik RWTH Aachen, Germany.

Redox Biology
|October 8, 2022
PubMed

Insights

Sustained activation of the Nrf2 pathway drives hepatic stem cell proliferation and dedifferentiation, leading to metastatic cancer. This Nrf2-β-catenin axis promotes liver tumorigenesis.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Hepatology

Background:

  • The Nrf2 signaling pathway is crucial in preventing cancer initiation.
  • However, activating mutations in Nrf2 are prevalent in various cancers, indicating a dual role.
  • The precise mechanisms behind Nrf2's contradictory functions remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which sustained Nrf2 activation contributes to cancer development.
  • To investigate the role of Nrf2 in hepatic progenitor cell transformation and tumorigenesis.
  • To identify the specific molecular players involved in Nrf2-driven liver cancer.

Main Methods:

  • Utilized a model of sustained Nrf2 activation in Wnt-responsive hepatic progenitor cells.
  • Analyzed cell proliferation, differentiation status, and metastatic potential.
  • Investigated the expression and activation of β-catenin in response to Nrf2 signaling.

Main Results:

  • Sustained Nrf2 activation induced proliferation and dedifferentiation of hepatic progenitor cells.
  • These transformed cells exhibited characteristics of metastatic cancer and resembled human hepatoblastoma.
  • Nrf2 activation led to increased β-catenin expression and its subsequent activation, driving malignant transformation.

Conclusions:

  • Identified a novel Nrf2-β-catenin signaling axis that promotes hepatic stem cell proliferation and triggers tumorigenesis.
  • Demonstrated that unbridled Nrf2 activation can drive liver cancer initiation and progression.
  • These findings highlight the critical role of Nrf2 levels in maintaining liver homeostasis and preventing oncogenesis.

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