Truncation of the TGF-β type II receptor gene results in insensitivity to TGF-β in human gastric cancer cells

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Abstract
The transforming growth factor-β (TGF-β receptor system has been implicated in the development of resistance to the growth-inhibitory effects of TGF-β. It has been reported that resistance to TGF-β correlates with inactivation of the TGF-β type II receptor (RII). In the present report, we examine the genetic changes in the TGF-β RII gene of human gastric cancer cell lines, SNU-5 and SNU-668, which we had previously reported to express truncated TGF-β RII transcripts. By independent PCR and Southern hybridization analysis of genomic DNA, we found that the genomic sequence of TGF-β RII is truncated after exon 2 in SNU-5 and after exon 3 in SNU-668. This was confirmed by sequencing the TGF-β RII cDNA cloned from a SNU-5 cDNA library. Predicted TGF-β RII protein of SNU-5 cells based on sequencing data contains only a part of extracellular domain of TGF-β RII. We demonstrate that cotransfection of 3TP-Lux and wild type TGF-β RII restores the TGF-β responsiveness in SNU-5 cells, suggesting that genetic changes in the TGF-β RII gene of SNU-5 cells are responsible for the loss of sensitivity to TGF-β. This is the first report demonstrating that truncation of the TGF-β RII gene is an alternative mechanism to inactivate the TGF-β signal transduction pathways.