up-regulation of sonic hedgehog contributes to tgf-β1-induced epithelial to mesenchymal transition in nsclc cells老年病的声波刺猬有助于tgf-β1-induced在nsclc细胞上皮间充质转变.pdfVIP

Up-Regulation of Sonic Hedgehog Contributes to TGF-b1-Induced Epithelial to Mesenchymal Transition in NSCLC Cells 1 2 1 2 1 Ma’in Y. Maitah , Shadan Ali , Aamir Ahmad , Shirish Gadgeel , Fazlul H. Sarkar * 1 Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, United States of America, 2 Division of Hematology/Oncology, Department of Internal Medicine, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, United States of America Abstract Background: Lung cancer, especially non-small cell lung cancer (NSCLC) is the major cause of cancer-related deaths in the United States. The aggressiveness of NSCLC has been shown to be associated with the acquisition of epithelial-to- mesenchymal transition (EMT). The acquisition of EMT phenotype induced by TGF-b1in several cancer cells has been implicated in tumor aggressiveness and resistance to conventional therapeutics; however, the molecular mechanism of EMT and tumor aggressiveness in NSCLC remains unknown. Methodology/Principal Findings: In this study we found for the first time that the induction of EMT by chronic exposure of A549 NSCLC cells to TGF-b1 (A549-M cells) led to the up-regulation of sonic hedgehog (Shh) both at the mRNA and protein levels causing activation of hedgehog signaling. These results were also reproduced in another NSCLC cell line (H2030). Induction of EMT was found to be consistent with aggressive characteristics such as increased clonogenic growth, cell motility and invasion. The aggressiveness of these cells was attenuated by the treatment of A549-M cells with pharmacological inhibitors of Hh signaling in addition to