Zhao, Y., Shao, G., Piao, C. Q., Berenguer, J. and Hei, T. K. Down-regulation of Betaig-h3 Gene is Involved in the Tumorigenesis in Human Bronchial Epithelial Cells Induced by Heavy-Ion Radiation. Radiat. Res. 162, 655–659 (2004).

High-energy (HZE) heavy ions, when compared to low-LET radiation, are highly effective in inducing gene mutation, chromosomal aberrations and neoplastic transformation. However, the underlying molecular mechanisms are not clearly understood. We have recently shown that the down-regulation of Betaig-h3 expression is causally linked to the tumorigenic phenotype of papillomavirus-immortalized human bronchial epithelial (BEP2D) cells treated with high-LET α-particle radiation. Using the BEP2D cell culture system, a radiation-induced transformation model has been established by a single 60-cGy dose of ⁵⁶Fe heavy-ion radiation. To determine whether the Betaig-h3 gene is involved in ⁵⁶Fe ion-induced tumorigenesis, the expression levels of the Betaig-h3 gene in tumorigenic cell lines and the ability of in vivo tumor suppression through the reintroduction of the Betaig-h3 gene in tumorigenic cells were determined. We found that the expression level of this gene is markedly decreased in three tumorigenic cell lines (⁵⁶FeT1–T3) compared with parental BEP2D cells. Ectopic expression of its cDNA in the ⁵⁶FeT2 tumorigenic cells significantly suppressed their tumorigenicity. Although biologically active TGFB1 is elevated in two of three tumorigenic cell lines, all these cell lines are resistant to the induction of Betaig-h3 expression by incubating the transformed cells with exogenous TGFB1 relative to control cells. Our data strongly suggest that down-regulation of Betaig-h3 expression results from the defect in the TGFB1 signaling pathway and plays a pivotal role in the tumorigenic process induced by ⁵⁶Fe heavy-ion radiation.