selective loss of tgfβ smad-dependent signalling prevents cell cycle arrest and promotes invasion in oesophageal adenocarcinoma cell lines选择性的损失tgfβsmad-dependent信号阻止细胞周期阻滞和促进入侵在食管腺癌细胞系.pdfVIP

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selective loss of tgfβ smad-dependent signalling prevents cell cycle arrest and promotes invasion in oesophageal adenocarcinoma cell lines选择性的损失tgfβsmad-dependent信号阻止细胞周期阻滞和促进入侵在食管腺癌细胞系.pdf

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selective loss of tgfβ smad-dependent signalling prevents cell cycle arrest and promotes invasion in oesophageal adenocarcinoma cell lines选择性的损失tgfβsmad-dependent信号阻止细胞周期阻滞和促进入侵在食管腺癌细胞系

Selective Loss of TGFb Smad-Dependent Signalling Prevents Cell Cycle Arrest and Promotes Invasion in Oesophageal Adenocarcinoma Cell Lines Benjamin A. Onwuegbusi, Jonathan R. E. Rees, Pierre Lao-Sirieix, Rebecca C. Fitzgerald* MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge, United Kingdom In cancer, Transforming Growth Factor b (TGFb) increases proliferation and promotes invasion via selective loss of signalling pathways. Oesophageal adenocarcinoma arises from Barrett’s oesophagus, progresses rapidly and is usually fatal. The contribution of perturbed TGFb signalling in the promotion of metastasis in this disease has not been elucidated. We therefore investigated the role of TGFb in Barrett’s associated oesophageal adenocarcinoma using a panel of cell lines (OE33, TE7, SEG, BIC, FLO). 4/5 adenocarcinoma cell lines failed to cell cycle arrest, down-regulate c-Myc or induce p21 in response to TGFb, and modulation of a Smad3/4 specific promoter was inhibited. These hyperproliferative adenocarcinoma cell lines displayed a TGFb induced increase in the expression of the extracellular matrix degrading proteinases, urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1), which correlated with an invasive cell phenotype as measured by in vitro migration, invasion and cell scattering assays. Inhibiting ERK and JNK pathways significantly reduced PAI and uPA induction and inhibited the invasive cell phenotype. These results suggest that TGFb Smad-dependent signalling is perturbed in Barrett’s carcinogenesis, resulting in failure of growth-arrest. However, TGFb can promote PAI and uPA expression and invasion through MAPK pathways. These data would support a dual role for TGFb in oesophageal adenocarcinoma. Citation: Onwuegbusi BA, Rees JRE, Lao-Sirieix P, Fitzgerald RC (2007) Selective Loss of TGFb Smad-Dependent Signalling Prevents Cell Cycle Arrest and Promotes Invasi