DRO1, a gene down-regulated by oncogenes, mediates growth inhibition in colon and pancreatic cancer cells
DRO1, a gene down-regulated by oncogenes, mediates growth inhibition in colon and pancreatic cancer cells
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DOI：
10.1074/jbc.m412593200
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发表时间：
2005-03-04
影响因子：
4.8
通讯作者：
Kolligs, FT
中科院分区：
文献类型：
--
作者：
Bommer, GT;Jäger, CJ;Kolligs, FT
人类组织中的肿瘤进展似乎受到一系列遗传和表观遗传改变的影响。在人类结直肠癌中，Wnt/β-连环蛋白/T细胞因子和RAS/RAF信号通路的缺陷在肿瘤的发生和进展中具有重要作用。迄今为止，关于β-连环蛋白激活后果的大部分研究都集中在那些被认为其表达被β-连环蛋白相关T细胞因子依赖性转录激活的基因上。很少有人知道的基因，其表达可能是下调继发于β-连环蛋白激活。使用消减抑制杂交方法，我们确定了一个基因的表达显着下降，在大鼠RK 3E上皮细胞肿瘤转化β-连环蛋白。由于该基因的表达在被其他几种癌基因转化的RK 3E中也被下调，因此该基因被命名为DRO 1，意为“被癌基因1下调”。“与相应的正常组织相比，DRO 1在结肠癌和胰腺癌细胞系以及大多数结直肠癌标本中的表达非常低。预测的DRO 1蛋白含有3个重复元件，与DRS/SRPX/ETX 1和SRPUL基因预测蛋白的羧基端区域具有显著的相似性，提示存在一个新的蛋白家族。在肿瘤转化的RK 3E或缺乏内源性DRO 1表达的结肠直肠癌和胰腺癌细胞系中，DRO 1的异位表达导致生长特性的实质性抑制。发现DRO 1抑制锚定非依赖性生长，并使细胞对失巢凋亡和CD 95诱导的凋亡敏感。我们的研究结果表明，抑制DRO 1表达可能是结肠直肠癌和胰腺癌发展中的一个重要事件。
Neoplastic progression in human tissues appears to be paralleled by a series of genetic and epigenetic alterations. In human colorectal cancers, defect Wnt/beta-catenin/T-cell factor and RAS/RAF signaling pathways have a major contributing role in tumor initiation and progression. To date, much of the research on the consequences of beta-catenin activation has been focused on genes whose expression is believed to be activated by beta-catenin-associated T-cell factor-dependent transcription. Little is known about genes whose expression may be down-regulated secondary to beta-catenin activation. Using a subtractive suppression hybridization approach, we identified a gene with markedly decreased expression in rat RK3E epithelial cells neoplastically transformed by beta-catenin. Because expression of this gene was also down-regulated in RK3E transformed by several other oncogenes, the gene was named DRO1 for " down-regulated by oncogenes 1." Compared with corresponding normal tissues, DRO1 expression was found to be very reduced in colon and pancreatic cancer cell lines as well as in most colorectal cancer specimens. The predicted DRO1 protein contains three repetitive elements with significant similarity to the carboxyl-terminal regions of the predicted proteins from DRS/SRPX/ETX1 and SRPUL genes, suggesting the existence of a new protein family. Ectopic expression of DRO1 in neoplastically transformed RK3E or colorectal and pancreatic cancer cell lines lacking endogenous DRO1 expression resulted in substantial inhibition of growth properties. DRO1 was found to suppress anchorage independent growth and to sensitize cells to anoikis and CD95-induced apoptosis. Our findings suggest that inhibition of DRO1 expression may be an important event in the development of colorectal and pancreatic cancers.