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Proteasome-dependent degradation of Smad7 is critical for lung cancer metastasis

Lu Tong1, Shihui Shen1, Quan Huang2

  • 1Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, 200241, Shanghai, China.

Cell Death and Differentiation
|November 27, 2019
PubMed

Insights

REGγ (proteasome activator) promotes lung cancer metastasis by degrading Smad7, activating TGF-β signaling. Targeting REGγ may offer new therapeutic strategies for aggressive lung cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Lung cancer exhibits high morbidity and mortality, with metastasis being a primary cause of death.
  • The precise mechanisms driving lung cancer metastasis remain incompletely understood.
  • Proteasome activators, such as REGγ, play roles in cellular processes that could influence cancer progression.

Purpose of the Study:

  • To investigate the role of REGγ in lung cancer metastasis.
  • To elucidate the molecular mechanisms by which REGγ influences cancer progression and metastasis.
  • To evaluate REGγ as a potential therapeutic target for lung cancer.

Main Methods:

  • Utilized a conditional Kras/p53 mutant mouse model for lung cancer.
  • Assessed tumor growth, size, and metastatic rates in REGγ-deficient versus wild-type mice.
  • Analyzed the TGFβ-Smad signaling pathway, including Smad7 degradation and E-cadherin/mesenchymal marker expression.
  • Correlated REGγ expression with patient data from lung cancer cohorts with metastasis.

Main Results:

  • REGγ deficiency significantly reduced tumor burden, metastasis, and improved survival in a mouse model.
  • REGγ promotes TGFβ-Smad signaling by ubiquitin-ATP-independent degradation of Smad7.
  • REGγ-positive lung cancer cells showed decreased E-cadherin and increased mesenchymal markers, indicative of epithelial-mesenchymal transition (EMT).
  • Overexpression of REGγ in human lung cancer patients correlated with metastasis, reduced E-Cadherin/Smad7 levels, and poor prognosis.

Conclusions:

  • REGγ drives lung cancer metastasis by enhancing TGF-β signaling through Smad7 degradation.
  • REGγ is associated with a more aggressive phenotype and poorer outcomes in lung cancer patients.
  • REGγ represents a promising novel therapeutic target for treating metastatic lung cancer.

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