The Overexpressed in Lung Cancer 1 (OLC1) gene is expressed at high levels in the majority of lung cancers, more often in samples from smokers than nonsmokers, and its expression is increased in cells treated with cigarette smoke.
Smoking increases the risk of lung cancer, but the mechanisms by which smoke triggers tumor formation are unknown. In earlier experiments, Shujun Cheng, M.D., of the Peking Union Medical College and the Chinese Academy of Medical Sciences in Beijing and colleagues identified 50 genes that were overexpressed in squamous cell carcinoma samples compared with normal lung epithelium.
In the current study, Cheng and colleagues tested the 50 genes for their ability to transform tissue culture cells. They examined the expression and gene amplification pattern of OLC1 in human tumor samples. They also tested the effects of overexpression of OLC1 in tissue culture and in a mouse model of lung cancer.
OLC1 overexpression transformed human fibroblast cells in culture and induced tumor formation in mice. The protein was overexpressed in the majority of human lung cancer samples tested, and the gene was amplified in the majority of lung tumor samples tested. High OLC1 protein expression was associated with smoking history in patient tissue samples. Exposure of cells in vitro to cigarette smoke increased OLC1 protein expression. Reduced expression of OLC1 in tissue culture cells increased cell death and decreased their ability to form colonies.
"Altogether, this study provides strong evidence supporting an important role for the novel gene OLC1 in the carcinogenesis of the human lung. The results indicate that cigarette smoke-induced overexpression of OLC1 may be involved at an early stage of human lung carcinogenesis," the authors write.
In an accompanying editorial, Frederic Kaye, M.D., of the National Cancer Institute and National Naval Medical Center in Bethesda, Md., acknowledges that the association of a previously uncharacterized gene with carcinogenesis provides exciting opportunities for research––and possibly for new treatments in the future. He cautions, however, that the new data on OLC1, also known as Ist1, should be considered preliminary. Researchers have criteria for which genes can be called oncogenes, including the existence of loss-of-function or gain-of-function mutations in human tumors. Therefore, he concluded, "we may need to reserve judgment on candidate cancer genes identified largely by functional data, such as Ist1/OLC1, until stronger supporting evidence for tumor-specific activation by gene amplification becomes available."
This research was published in the Journal of the National Cancer Institute November 11, 2008.
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