Ullmannova Veronika, Popescu Nicholas C
Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Int J Oncol. 2006 Nov;29(5):1127-32.
Several years after the isolation of deleted in liver cancer 1 (DLC-1), a gene that encodes a Rho GTPase activating protein, the closely related DLC-2 gene was identified. DLC-1 and DLC-2 are approximately 50% identical and share the same SAM-RhoGAP-START domain organization. Since DLC-1 and -2 are located at chromosome regions that are commonly deleted in cancer cells and have been found to function as tumor suppressor genes, we sought to compare their expression profiles in several common types of cancer and to determine whether dlc1 and dlc2 proteins cooperate in tumor development. Using cancer-profiling arrays, we detected for the first time down-regulation of DLC-1 expression in renal, uterine and rectal cancers and down-regulation of DLC-2 expression in lung, ovarian, renal, breast, uterine, gastric, colon and rectal tumors. Since DLC-1 also functions as a metastasis suppressor gene in breast cancer, DLC-1 and DLC-2 expression were examined in a series of primary ductal carcinomas derived from patients with regional lymph node metastases. Using quantitative RT-PCR we detected a significantly lower expression of DLC-1 and DLC-2 in high percentage of tumors, suggesting that deficiency of either DLC gene facilitates dissemination of breast carcinoma cells to secondary sites. We examined DLC-2 expression in DLC-1-negative cell lines derived from human breast, non-small cell lung, and hepatocellular carcinomas, that could be rendered less or non-tumorigenic by ectopic expression of DLC-1. DLC-2 transcripts were detected in all cell lines, indicating that none of the cells were deficient in both members of the DLC family. This comparative expression analysis of DLC-1 and -2 identifies down-regulation of the two emerging bona fide tumor suppressor genes in additional types of solid tumors. The large spectrum of cancers with dysregulated DLC genes underlines the involvement of this family of genes in cancer development.
在肝癌缺失基因1（DLC-1，一种编码Rho GTP酶激活蛋白的基因）被分离出来几年后，与之密切相关的DLC-2基因被鉴定出来。DLC-1和DLC-2约50%相同，且具有相同的SAM-RhoGAP-START结构域组织。由于DLC-1和-2位于癌细胞中常被缺失的染色体区域，并且已被发现具有肿瘤抑制基因的功能，我们试图比较它们在几种常见癌症类型中的表达谱，并确定dlc1和dlc2蛋白在肿瘤发展中是否协同作用。使用癌症分析阵列，我们首次检测到肾癌、子宫癌和直肠癌中DLC-1表达下调，以及肺癌、卵巢癌、肾癌、乳腺癌、子宫癌、胃癌、结肠癌和直肠癌中DLC-2表达下调。由于DLC-1在乳腺癌中也起着转移抑制基因的作用，我们检测了一系列来自有区域淋巴结转移患者的原发性导管癌中DLC-1和DLC-2的表达。使用定量逆转录聚合酶链反应，我们在高比例的肿瘤中检测到DLC-1和DLC-2的表达显著降低，这表明任何一种DLC基因的缺陷都有助于乳腺癌细胞扩散到继发部位。我们检测了源自人乳腺癌、非小细胞肺癌和肝癌的DLC-1阴性细胞系中DLC-2的表达，这些细胞系通过DLC-1的异位表达可使其致癌性降低或消失。在所有细胞系中都检测到了DLC-转录本，这表明没有一个细胞在DLC家族的两个成员中都存在缺陷。对DLC-1和-2的这种比较表达分析确定了这两个新出现的真正肿瘤抑制基因在其他类型实体瘤中的下调。DLC基因失调的癌症种类繁多，突显了该基因家族在癌症发展中的作用。
