Park Do Youn, Sakamoto Hideo, Kirley Sandra D, Ogino Shuji, Kawasaki Takako, Kwon Eunjeong, Mino-Kenudson Mari, Lauwers Gregory Y, Chung Daniel C, Rueda Bo R, Zukerberg Lawrence R
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Am J Pathol. 2007 Nov;171(5):1509-19. doi: 10.2353/ajpath.2007.070331.
Cables is a cyclin-dependent kinase-binding nuclear protein that maps to chromosome 18q11-12. Here, we assessed Cables expression in 160 colorectal cancers (CRCs), its role in colon cancer cell growth, and the potential mechanisms of Cables inactivation. Expression levels, promoter methylation, and mutational status of Cables were investigated in colon cancer cell lines and primary colon tumors. Chromosome 18q loss of heterozygosity (LOH) was evaluated with multiple polymorphic markers. Cables inhibited cellular proliferation and colony formation in colon cancer cell lines. Cables expression was reduced in 65% of primary CRCs. No mutations were detected in 10 exons of Cables in 20 primary colon tumors. Cables promoter was methylated in cell lines with decreased Cables expression and vice versa. 5-Aza-2'-deoxycytidine resulted in increased Cables expression in methylated cell lines. There was a significant correlation between promoter methylation and Cables gene expression in primary colon tumors. Sixty-five percent of primary colon tumors demonstrated chromosome 18q LOH. LOH involving the Cables region was observed in 35% of cases, including those in which more distal portions of chromosome 18q were retained, and Cables expression was decreased in all such cases. Loss of Cables expression in 65% of CRCs suggests that it is a common event in colonic carcinogenesis, with promoter methylation and LOH appearing to be important mechanisms of Cables gene inactivation.
Cables是一种细胞周期蛋白依赖性激酶结合核蛋白，定位于染色体18q11 - 12。在此，我们评估了160例结直肠癌（CRC）中Cables的表达、其在结肠癌细胞生长中的作用以及Cables失活的潜在机制。研究了结肠癌细胞系和原发性结肠肿瘤中Cables的表达水平、启动子甲基化和突变状态。用多个多态性标记评估染色体18q杂合性缺失（LOH）。Cables抑制结肠癌细胞系中的细胞增殖和集落形成。65%的原发性CRC中Cables表达降低。在20例原发性结肠肿瘤的Cables的10个外显子中未检测到突变。在Cables表达降低的细胞系中，Cables启动子发生甲基化，反之亦然。5 - 氮杂 - 2'-脱氧胞苷导致甲基化细胞系中Cables表达增加。原发性结肠肿瘤中启动子甲基化与Cables基因表达之间存在显著相关性。65%的原发性结肠肿瘤表现出染色体18q LOH。在35%的病例中观察到涉及Cables区域的LOH，包括那些保留了染色体18q更远端部分的病例，并且在所有这些病例中Cables表达均降低。65%的CRC中Cables表达缺失表明其在结肠癌发生中是一个常见事件，启动子甲基化和LOH似乎是Cables基因失活的重要机制。
