Decreased expression of thrombomodulin is correlated with tumor cell invasiveness and poor prognosis in nonsmall cell lung cancer

Abstract

Thrombomodulin (TM) plays a role in coagulation, inflammation, and cell adhesion. Reduction of TM expression plays an important role in the tumor metastatic process; however, insufficient information is available regarding the expression of TM in nonsmall cell lung cancer (NSCLC). Sixty NSCLC patients who underwent surgery were reviewed for TM expression and multiple variables were assessed by univariate and multivariate analyses. The expression level of TM and its metastatic ability were examined in vitro using the human NSCLC A549 cell line. TM expression in NSCLC was significantly correlated with survival; the 5-yr survival rates of patients with high and low TM expression were 23% and 18% (P < 0.01), respectively. Distribution of TM was detected predominantly in the normal lung tissue compared with lung cancer tissue. Western blot analysis showed, on average, decreased expression levels of TM protein in the lung cancer tissues of patients with NSCLC. An in vitro study also showed that overexpression of TM can inhibit the invasiveness and migration ability of the A549 cell line, whereas silencing of TM significantly enhanced these processes. This inhibition of cellular migration by overexpression of TM was significantly prevented by the selective inhibitors of PI3K and Akt, but not by MAPK inhibitors. This study demonstrates that a decrease in TM expression may be an indicator in the prognosis of NSCLC patients and provides new insights into the molecular mechanisms of TM in the metastasis of NSCLC. ? 2010 Wiley-Liss, Inc.