Proteasome-dependent degradation of Smad7 is critical for lung cancer metastasis.
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| 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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| Authors | Lu Tong, Shihui Shen, Quan Huang, Junjiang Fu, Tianzhen Wang, Linian Pan, Pei Zhang, Geng Chen, Tingmei Huang, Ke Li, Qingwu Liu, Shaofang Xie, Xiao Yang, Robb E Moses, Xiaotao Li, Lei Li |
| Journal | Cell death and differentiation (Cell Death Differ) Vol. 27 Issue 6 Pg. 1795-1806 (06 2020) ISSN: 1476-5403 [Electronic] England |
| PMID | 31767934 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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