Restoration of TGF-β signalling reduces tumorigenicity in human lung cancer cells

Members of the transforming growth factor-beta (TGF-beta) family regulate a wide range of biological processes including cell proliferation, migration, differentiation, apoptosis, and extracellular matrix deposition. Resistance to TGF-beta-mediated tumour suppressor function in human lung cancer may occur through the loss of type II receptor (T beta RII) expression. In this study, we investigated the expression pattern of T beta RII in human lung cancer tissues by RT-PCR and Western blot analyses. We observed downregulation of T beta RII in 30 out of 46 NSCLC samples (65%) by semiquantitative RT-PCR. Western blot analyses with tumour lysates showed reduced expression of T beta RII in 77% cases. We also determined the effect of T beta RII expression in lung adenocarcinoma cell line (VMRC-LCD) that is not responsive to TGF-beta due to lack of T beta RII expression. Stable expression of T beta RII in these cells restored TGF-beta-mediated effects including Smad2/3 and Smad4 complex formation, TGF-beta-responsive reporter gene activation, inhibition of cell proliferation and increased apoptosis. Clones expressing T beta RII showed reduced colony formation in soft-agarose assay and significantly reduced tumorigenicity in athymic nude mice. Therefore, these results suggest that reestablishment of TGF-beta signalling in T beta RII null cells by stable expression of T beta RII can reverse malignant behaviour of cells and loss of T beta RII expression may be involved in lung tumour progression.