Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer.
Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer.
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发表时间：
2000-02
期刊：
影响因子：
11.2
通讯作者：
R. J. Guan;H. Ford;Yineng Fu;Youzhi Li;Leslie M. Shaw;A. Pardee
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文献类型：
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作者：
R. J. Guan;H. Ford;Yineng Fu;Youzhi Li;Leslie M. Shaw;A. Pardee
一个与细胞分化相关的基因通过差异显示被鉴定为结肠癌转移的候选抑制基因。该基因的全长cDNA为3 kb，在正常结肠和原发性结肠癌组织和细胞系中表达，但在其转移性对应物中不表达。GenBank检索发现，它与最近克隆的基因，分化相关基因-1（Drg-1）相同，该基因分离自分化的HT-29结肠癌细胞。稳定转染的SW 620转移性结肠癌细胞系与Drg-1 cDNA诱导的形态学变化与分化一致，上调几个结肠上皮细胞分化标志物（碱性磷酸酶，癌胚抗原，和E-钙粘蛋白）的表达。此外，Drg-1的表达由几种已知的细胞分化试剂控制，例如过氧化物酶体增殖物激活受体γ（曲格列酮和BRL 46593）和类维生素A X受体（LG 268）的配体，以及组蛋白脱乙酰酶抑制剂（曲格列酮A、辛二酰苯胺异羟肟酸和三丁酸甘油酯）。三丁酸甘油酯和低剂量的5 '-氮杂-2'-脱氧胞苷（100 nM）（DNA甲基化抑制剂）联合使用可协同诱导Drg-1表达。功能研究表明，在转移性结肠癌细胞中过表达Drg-1减少了通过Matrigel的体外侵袭，并抑制了裸鼠体内肝转移。我们提出Drg-1通过诱导结肠癌细胞分化和部分逆转转移表型来抑制结肠癌转移。
A gene related to cell differentiation was identified by differential display as a candidate suppressor of metastases in colon cancer. This gene, with a full-length cDNA of 3 kb, is expressed in normal colon and primary colon cancer tissues and cell lines but not in their metastatic counterparts. A GenBank search found that it is identical to a recently cloned gene, differentiation-related gene-1 (Drg-1), isolated from differentiated HT-29 colon cancer cells. Stable transfection of the SW620 metastatic colon cancer cell line with Drg-1 cDNA induced morphological changes consistent with differentiation and up-regulated the expression of several colonic epithelial cell differentiation markers (alkaline phosphatase, carcinoembryonic antigen, and E-cadherin). Moreover, the expression of Drg-1 is controlled by several known cell differentiation reagents, such as ligands of peroxisome proliferator-activated receptor gamma (troglitazone and BRL46593) and of retinoid X receptor (LG268), and histone deacetylase inhibitors (trichostatin A, suberoylanilide hydroxamic acid, and tributyrin). A synergistic induction of Drg-1 expression was seen with the combination of tributyrin and a low dose of 5'-aza-2'-dexoycytidine (100 nM), an inhibitor of DNA methylation. Functional studies revealed that overexpression of Drg-1 in metastatic colon cancer cells reduced in vitro invasion through Matrigel and suppressed in vivo liver metastases in nude mice. We propose that Drg-1 suppresses colon cancer metastasis by inducing colon cancer cell differentiation and partially reversing the metastatic phenotype.