2. Academic Validation
  3. Proteasome-dependent degradation of Smad7 is critical for lung cancer metastasis

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

  • Cell Death Differ. 2020 Jun;27(6):1795-1806. doi: 10.1038/s41418-019-0459-6.
Lu Tong  # 1,  Shihui Shen  # 1,  Quan Huang  # 2,  Junjiang Fu  # 3,  Tianzhen Wang 1,  Linian Pan 1,  Pei Zhang 4,  Geng Chen 1,  Tingmei Huang 1,  Ke Li 1,  Qingwu Liu 1,  Shaofang Xie 1,  Xiao Yang 5,  Robb E Moses 6,  Xiaotao Li 7,  Lei Li 8
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, 200241, Shanghai, China.
  • 2 Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, 200003, Shanghai, China.
  • 3 Key Laboratory of Epigenetics and Oncology, the Research Center for Preclinical Medicine, Southwest Medical University, 646000, Sichuan, China.
  • 4 Department of Pathology, the Second Chengdu Municipal Hospital, 610017, Chengdu, China.
  • 5 State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, 100071, Beijing, China.
  • 6 Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
  • 7 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, 200241, Shanghai, China. [email protected].
  • 8 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, 200241, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 31767934 DOI: 10.1038/s41418-019-0459-6
Abstract

Lung Cancer is one of the cancers with highest morbidity and mortality rates and the metastasis of lung Cancer is a leading cause of death. Mechanisms of lung Cancer metastasis are yet to be fully understood. Herein, we demonstrate that mice deficient for REGγ, a Proteasome activator, exhibited a significant reduction in tumor size, numbers, and metastatic rate with prolonged survival in a conditional Kras/p53 mutant lung Cancer model. REGγ enhanced the TGFβ-Smad signaling pathway by ubiquitin-ATP-independent degradation of Smad7, an inhibitor of the TGFβ pathway. Activated TGFβ signaling in REGγ-positive lung Cancer cells led to diminished expression of E-cadherin, a biomarker of epithelial-mesenchymal transitions (EMT), and elevated mesenchymal markers compared with REGγ-deficient lung Cancer cells. REGγ overexpression was found in lung Cancer patients with metastasis, correlating with the reduction of E-Cadherin/Smad7 and a poor prognosis. Overall, our study indicates that REGγ promotes lung Cancer metastasis by activating TGF-β signaling via degradation of Smad7. Thus, REGγ may serve as a novel therapeutic target for lung cancers with poor prognosis.

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