Thrombomodulin Inhibits Tumorigenesis And Migration Of Lung Cancer Cells And Its Mechanism

Thrombomodulin is an endothelial cell membrane protein and plays critical roles in anti-thrombosis, anti-inflammation, vascular endothelial protection, and is traditionally regarded as a “vascular protection god”. In recent years, thrombomodulin has been reported to be down-regulated in variety of malignant tumors including lung cancer. Noticeably, reduction of thrombomodulin expression is associated with poor prognosis of the cancer patients; however, the role and mechanism of thrombomodulin in lung cancer are enigmatic. In this study, we found that induction of thrombomodulin overexpression in lung cancer cells by cholesterol-reducing drug atorvastatin significantly diminished the tumorigenic capability of the cells. Moreover, we demonstrated that overexpression of thrombomodulin inhibited tumor cell growth, caused G0/G1 phase arrest, and markedly reduced the colony forming capability of the lung cancer cells. Furthermore, overexpression of thrombomodulin inhibited cell migration and invasion. Molecular mechanistic study revealed that thrombomodulin up-regulated E-cadherin but downregulated N-cadherin expression, resulting in reversal of EMT in the lung cancer cells anddiminishing tumoigenecity. Moreover, silencing TM expression led to decreased Ecadherin and increased N-cadherin. Taken together, our study implies that atorvastatin exerts its anti-cancer tumorigenic effect through inducing thrombomodulin overexpression. Our findings suggestthat thrombomodulin functions as a tumor suppressive protein, providing a conceptual framework for inducing thrombomodulin overexpression as a sensible strategy and approach for TM-based gene therapy and using atorvastatin as an anti-cancer drug.