DLC-1 tumor suppressor regulates CD105 expression on human non-small cell lung carcinoma cells through inhibiting TGF-β1 signaling.

Acquisition of features of mesenchymal cells represents a key step of metastatic progression of cancer cells and searching for mechanisms underlying the acquisition will help design novel clinical strategies for suppressing the metastatic progression. The Deleted in Liver Cancer-1 (DLC-1) gene is a p122/RhoGAP tumor/metastatic suppressor gene. However, the mechanism underlying DLC-1's inhibition of metastasis still remains largely unknown. In this study, we revealed that the DLC-1-deficient, but not the DLC-1-competent, human non-small cell lung carcinoma cells (NSCLCs) could acquire the TGF-β1-induced expression of CD105, a common surface marker of mesenchymal stem cells, with consequent increase in CD105-associated cell motility. Interestingly, the induced CD105 expression and cell motility were subjected to the inhibition by the DLC-1-RhoA-Rock1 signaling through inhibiting the serine phosphorylation at a linker region, but not at the C-terminus, of the Smad3 protein and Smad3 protein nuclear translocation down the canonical TGF-β1 signaling. In addition, the evidence suggested that DLC-1 very likely exerted its inhibitory effects on the TGF-β1 signaling and the associated CD105 acquisition in both the cytoplasm and the nucleus. Consistent to the in vitro findings, a reverse correlation between CD105 and DLC-1 in protein expression was identified in primary NSCLC tissues and their surrounding non-tumor tissues. In summary, this study revealed a novel anti-metastasis mechanism governed by the DLC-1 tumor/metastasis suppressor, thus helping design new diagnostic and therapeutic approaches for NSCLCs.