Down-regulation ofBetaig-h3Gene is Involved in the Tumorigenesis in Human Bronchial Epithelial Cells Induced by Heavy-Ion Radiation

Abstract

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 alpha-particle radiation. Using the BEP2D cell culture system, a radiation-induced transformation model has been established by a single 60-cGy dose of (56)Fe heavy-ion radiation. To determine whether the Betaig-h3 gene is involved in (56)Fe 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 ((56)FeT1-T3) compared with parental BEP2D cells. Ectopic expression of its cDNA in the (56)FeT2 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 (56)Fe heavy-ion radiation.

BigH3 protein expression as a marker for breast cancer

“…Although biologically active TGF-ß1 was elevated in two of three tumorigenic cell lines, all these cell lines were resistant to the induction of BigH3 expression when BigH3 expression was analyzed. Such data strongly suggest that downregulation of BigH3 expression resulted from the defect in the TGF-ß1 signalling pathway and played a pivotal role in the tumorigenic process induced by 56 Fe heavy-ion radiation (53). Other studies (53,54) have indicated that the expression of the BigH3 gene was downregulated or lost in a variety of tumor cell lines derived from lung, prostate, mammary, and kidney tumors.…”

“…Such data strongly suggest that downregulation of BigH3 expression resulted from the defect in the TGF-ß1 signalling pathway and played a pivotal role in the tumorigenic process induced by 56 Fe heavy-ion radiation (53). Other studies (53,54) have indicated that the expression of the BigH3 gene was downregulated or lost in a variety of tumor cell lines derived from lung, prostate, mammary, and kidney tumors. The results showed that the BigH3 gene was expressed at a relatively high level in normal and immortalized cell lines, whereas it was downregulated in most of the tumor cell lines.…”

Epigenetic Inactivation of Betaig-h3 Gene in Human Cancer Cells

“…This gene product is composed of 683 amino acids containing four homologous internal repeat domains (Fas-1) and has been reported to function as an extracellular matrix protein to mediate cell adhesion and migration through interacting with integrin (a 3 h 1 , a v h 3 , and a v h 5 ), collagen (I, IV, and VI), laminin, and fibronectin (8,9). In addition, Betaig-h3 is involved in cell growth, cell differentiation, wound healing, apoptosis, and tumorigenesis (10)(11)(12)(13). Betaig-h3 gene mutations were identified in families affected with human autosomal dominant corneal dystrophies (14).…”

“…In addition, a novel class of TSGs has been identified where epigenetic inactivation plays the predominant role, whereas somatic mutations are a relatively rare event (16,17). We have shown previously that Betaig-h3 gene is ubiquitously expressed in normal human tissues, whereas its expression was either down-regulated or lost in a variety of human tumor cell lines (11)(12)(13). Downregulation of this gene has been shown to correlate with the tumorigenic phenotype in human bronchial epithelial cells, suggesting an antitumor function of this gene (12,13).…”

Genetic Effects of X-Ray and Carbon Ion Irradiation in Head and Neck Carcinoma Cell Lines

“…It is an area of active investigation to elucidate the mechanisms underlying the increased biologic effectiveness of dense irradiation. Several studies have evaluated the correlation between tumor responses to carbon ion irradiation and the expression status of known genes 11,13,38,41) . Irradiation with high LET carbon ion beams caused glioma cells with either the wild-type or mutant p53 gene to fail to proliferate and apoptosis, more effectively than X-rays 15) .…”