Oncogenic ras induces gastrin gene expression in colon cancer
Oncogenic ras induces gastrin gene expression in colon cancer
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DOI：
10.1016/s0016-5085(98)70085-x
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发表时间：
1998-11-01
期刊：
影响因子：
29.4
通讯作者：
Tillotson, LG
中科院分区：
文献类型：
--
作者：
Nakata, H;Wang, SL;Tillotson, LG
背景与目的：胃泌素作为一种肿瘤生长因子，在部分结肠癌组织中的表达明显高于正常组织。本研究的目的是阐明结肠癌胃泌素诱导的转录机制。方法：检测结肠癌细胞株和手术标本中胃泌素信使(Gastin Messenger，mRNA)水平和K-ras基因分型。将ras癌基因表达载体导入结肠癌细胞，用胃泌素-荧光素酶报告基因检测其转录活性。结果：与野生型相比，K-ras突变的结肠癌细胞株和组织中胃泌素基因的表达水平均显著升高。用丝裂原活化蛋白激酶抑制剂PD98059处理几个ras突变细胞系后，内源性胃泌素mRNA水平下降。Ras对胃泌素表达的影响可能是通过胃泌素启动子介导的，因为癌基因ras和活化的raf表达载体都诱导了胃泌素启动子和荧光素酶报告基因。RAF的显性负性形式和细胞外调节激酶的共表达可阻断致癌ras的诱导作用。结论：致癌ras通过激活Raf-MEK-ERK信号转导通路诱导胃泌素基因表达。
Background & Aims: The expression of gastrin, as a tumor growth factor, is significantly increased in some colon cancers compared with the low levels found in normal mucosa. The aim of this study was to elucidate the transcriptional mechanisms of gastrin induction in colon cancer. Methods: Gastrin messenger (mRNA) levels and K-ras genotype were determined in colon cancer cell lines and surgical specimens. Colon cancer cells were transfected with oncogenic ras expression vectors, and transcriptional activity was assayed with gastrin-luciferase reporter genes. Results: Colon cancer cell lines and tissues with K-ras mutations all had significantly higher gastrin mRNA levels than those that were ras wild type. Treatment of several ras mutant cell lines with PD98059, an inhibitor of mitogen-activated protein kinase kinase, resulted in a decrease in endogenous gastrin mRNA levels. The effects of ras on gastrin expression appeared to be mediated through the gastrin promoter because transfection of oncogenic ras and activated raf expression vectors both induced gastrin-promoter, luciferase-reporter genes. The inductive effects of oncogenic ras could be blocked by the coexpression of dominant negative forms of raf and extracellular regulated kinase. Conclusions: Oncogenic ras induces gastrin gene expression through activation of the Raf-MEK-ERK signal transduction activation pathway.