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

摘要

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 REG gamma, 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. REG gamma enhanced the TGF beta-Smad signaling pathway by ubiquitin-ATP-independent degradation of Smad7, an inhibitor of the TGF beta pathway. Activated TGF beta signaling in REG gamma-positive lung cancer cells led to diminished expression of E-cadherin, a biomarker of epithelial-mesenchymal transitions (EMT), and elevated mesenchymal markers compared with REG gamma-deficient lung cancer cells. REG gamma 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 REG gamma promotes lung cancer metastasis by activating TGF-beta signaling via degradation of Smad7. Thus, REG gamma may serve as a novel therapeutic target for lung cancers with poor prognosis.