Tumor suppressor function of Betaig-h3 gene in radiation carcinogenesis

Full text: Interaction between cell and extracellular matrix (ECM) plays a crucial role in tumor invasiveness and metastasis. Using an immortalized human bronchial epithelial (BEP2D) cell model, we showed previously that expression of a list of genes including Betaig-h3 (induced by transforming growth factor-beta), DCC (deleted in colorectal cancer), p21cip1, c-fos, Heat shock protein (HSP27) and cytokeratin 14 were differentially expressed in several independently generated, radiation-induced tumor cell lines (TL1-TL5) relative to parental BEP2D cells. Our previous data further demonstrated that loss of tumor suppressor gene(s) as a likely mechanism of radiation carcinogenesis. In the present study, we chose Betaig-h3 and DCC that were downregulated in tumorigenic cells for further study. Restored expression of Betaig-h3 gene, not DCC gene, by transfecting cDNA into tumor cells resulted in a significant reduction in tumor growth. Furthermore, exogenous TGF-beta1 induced expression of Betaig-h3 gene and inhibited the growth of both control and tumorigenic BEP2D cells. The data suggest that downregulation of Betaig-h3 gene may result from the decreased expression of upstream mediators such as TGF-beta . In addition, Betaig-h3 gene is ubiquitously expressed in various normal human tissues with exception of the brain. However, there was a decrease or absence in expression of Betaig-h3 gene in 14 human tumor cell lines of diverse histological types examined, when compared with normal human cells or tissues. The findings provide strong evidence that the Betaig-h3 gene has tumor suppressor function in radiation-induced tumorigenic human bronchial epithelial cells and suggest a potential target for interventional therapy