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Dlc-1, a new tumor suppressor gene for human non-small-cell lung carcinomas as well as other common kinds of cancer.
Yuan-BS; Jefferson-AM; Baldwin-KT; Reynolds-SH
Proceedings of the American Association for Cancer Research (AACR) 94th Annual Meeting, July 11-14, 2003, Washington, DC. 2nd edition. Philadelphia, PA: American Association for Cancer Research, 2003 Jul; 44:592
DLC-1 (Deleted in Liver Cancer) was originally isolated from a liver cancer tissue as a candidate tumor suppressor gene. It is localized on human chromosome 8p22, a region frequently deleted in several common kinds of human cancer including liver, breast and lung cancers. One of three well-characterized domains in DLC-1 gene is the GTPase Activating Protein (GAP) domain, which can inactivate RhoA, a member of Ras oncogene superfamily. In previous studies, down-regulation of DLC-1 was found in 28% of liver, 70% of breast, 70% of colon and in 50% of prostate tumor cell lines. Genomic deletion of DLC-1 was observed in 40% of primary liver and breast cancers, and in 90% of liver cancer cell lines. DLC-1 is also a hypermethylated gene. DNA hypermethylation in the promoter region of DLC-1 was found in liver, breast, colon and prostate cancer cell lines and is directly associated with the down-regulation of the gene. Cell growth inhibition by DLC-1 in an in vitro cell proliferation assay was observed in both liver and breast cancer cell lines. Complete suppression of tumorigenicity was observed in breast cancer cells injected into nude mice after DLC-1 gene transfection. Our new studies of DlC-1 on human non-small cell lung carcinoma (NSCLC) cell lines suggest that DLC-1 is also a bona fide tumor suppressor gene for lung cancer. Decreased or no expression of DLC-1 gene was found by RT -PCR in 11 out of 19 NSCLC cell lines. Of these 11 cell lines, nine showed re-expression of the gene after treatment with 5-aza-2'-deoxycytidine, a DNA demethylation agent. Promoter DNA hypermethylation was detected by Southern blot analysis in 80% of human NSCLC cell lines showing down-regulation of the DLC-1. Significant in vitro growth inhibition was observed in four NSCLC cell lines after transfection with the DLC-1 gene a an in vitro cell proliferation assay. To date, in an in vivo nude mice tumorigenicity assay, complete suppression of tumor growth was observed in two of three NSCLC cell lines transfected with DLC-1 . The combined data suggests that DLC-1 may be a new important tumor suppressor gene for several kinds of human cancer that is frequently targeted and inactivated either by genomic deletion, as in human liver and breast cancers, or by DNA hypermethylation, as in human lung cancer.
Tumors; Tumorigenesis; Cancer; Cell-biology; Cell-damage; Cell-function; Cellular-function; Lung-cancer; Lung-disorders; Genetic-factors; Genetic-disorders; Genetics; Carcinogenesis; Liver-cancer; Liver-cells; Breast-cancer
Abstract; Conference/Symposia Proceedings
Proceedings of the American Association for Cancer Research (AACR) 94th Annual Meeting, July 11-14, 2003, Washington, DC. 2nd edition