机构：[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
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.
基金：
This work was supported by the National Basic
Research Program of China (2016YFC0902102, 2015CB910402).
This study was also funded by the National Basic Research Program
(2011CB504200, 2015CB910403). This work was also supported in
part by grants from National Natural Science Foundation of China
(81401837, 81471066, 81672887, 81261120555, 31200878,
31071875, 81271742, 31401012, 31730017), the Science and Technology
Commission of Shanghai Municipality (19140900400,
14430712100), Shanghai Rising-Star Program (16QA1401500),
Shanghai natural science foundation (17ZR1407900, 12ZR1409300,
14ZR1411400) and project funded by China Postdoctoral Science
Foundation(2019M651434).
第一作者机构：[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
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Lu Tong,Shihui Shen,Quan Huang,et al.Proteasome-dependent degradation of Smad7 is critical for lung cancer metastasis.[J].CELL DEATH AND DIFFERENTIATION.2020,27(6):1795-1806.doi:10.1038/s41418-019-0459-6.
APA：
Lu Tong,Shihui Shen,Quan Huang,Junjiang Fu,Tianzhen Wang...&Lei Li.(2020).Proteasome-dependent degradation of Smad7 is critical for lung cancer metastasis..CELL DEATH AND DIFFERENTIATION,27,(6)
MLA：
Lu Tong,et al."Proteasome-dependent degradation of Smad7 is critical for lung cancer metastasis.".CELL DEATH AND DIFFERENTIATION 27..6(2020):1795-1806
生物学