Reduced expression of RAS protein activator like-1 in gastric cancer
Reduced expression of RAS protein activator like-1 in gastric cancer
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DOI：
10.1002/ijc.25459
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发表时间：
2011-03-15
影响因子：
6.4
通讯作者：
Omata, Masao
中科院分区：
文献类型：
--
作者：
Seto, Motoko;Ohta, Miki;Omata, Masao
RAS信号在人类肿瘤中经常失调。然而，RAS突变仅在一小部分人胃癌中发现，这暗示了胃肿瘤发生中RAS信号激活的其他机制。我们以前曾报道过RAS蛋白激活物样-1（RASAL 1）（RAS-GT3激活蛋白中关闭RAS活性的一员）的表达减少有助于结肠肿瘤的进展。在我们的研究中，我们探讨了RASAL 1表达减少在胃癌发生中的作用。免疫印迹法检测10个胃癌细胞系中有6个RASAL 1表达降低。RASAL 1的敲低增加了对生长因子刺激的丝裂原活化蛋白激酶信号传导，并且RASAL 1的强制表达降低了胃癌细胞的增殖。免疫组化分析显示，RASAL 1在48例胃癌中的23例（48%）表达降低，但在腺瘤中无表达（0/10）。RASAL 1基因启动子区的甲基化和杂合性缺失（洛）在RASAL 1基因座进行了检查，以调查RASAL 1沉默的原因。所有RASAL 1减少的细胞系都有RASAL 1甲基化，两个有洛缺失。在原发性胃癌中，50%（6/12）RASAL 1降低的患者检测到甲基化或洛缺失。此外，RASAL 1表达恢复在一些细胞系组蛋白去乙酰化酶抑制剂治疗。我们的研究结果表明，RASAL 1表达减少，部分原因是遗传和表观遗传变化，有助于胃癌的发生，也再次强调RAS信号在胃癌发展中的重要性。
RAS signaling is frequently deregulated in human neoplasms. However, RAS mutations have been found in only a small proportion of human gastric cancers, implicating other mechanisms in the activation of RAS signaling in gastric tumorigenesis. We have previously reported that decreased expression of RAS protein activator like-1 (RASAL1), a member of the RAS-GTPase-activating proteins that switch off RAS activity, contributes to colon tumor progression. In our study, we explored the involvement of decreased RASAL1 expression in gastric tumorigenesis. RASAL1 expression was reduced in 6 of 10 gastric cancer cell lines examined by immunoblotting. Knockdown of RASAL1 increased mitogen-activated protein kinase signaling in response to growth factor stimulation, and the forced expression of RASAL1 reduced proliferation of gastric cancer cells. Immunohistochemical analyses in primary gastric tumors showed that RASAL1 expression was reduced in 23 of 48 (48%) of the gastric cancers but in none of the adenomas (0/10). Methylation of the RASAL1 promoter region and loss of heterozygosity (LOH) at the RASAL1 locus were examined to investigate the causes of RASAL1 silencing. All cell lines with reduced RASAL1 had RASAL1 methylation, and two had LOH. In primary gastric cancers, methylation or LOH was detected in 50% (6/12) of those with reduced RASAL1. Furthermore, RASAL1 expression was restored in some cell lines by histone deacetylase inhibitor treatment. Our findings demonstrate that reduced RASAL1 expression, partly due to genetic and epigenetic changes, contributes to gastric carcinogenesis, and also re-emphasize the importance of RAS signaling in gastric cancer development.