Transforming Growth Factor β and Ras/MEK/ERK Signaling Regulate the Expression Level of a Novel Tumor Suppressor Lefty
Transforming Growth Factor β and Ras/MEK/ERK Signaling Regulate the Expression Level of a Novel Tumor Suppressor Lefty
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DOI：
10.1097/mpa.0b013e31823b66d3
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发表时间：
2012-07-01
期刊：
影响因子：
2.9
通讯作者：
Hibi, Toshifumi
中科院分区：
文献类型：
--
作者：
Miyata, Naoteru;Azuma, Toshifumi;Hibi, Toshifumi
目的：(1)寻找一种新的受转化生长因子(TGF-β)调控的抑癌基因；(2)探讨Ras/MEK/ERK信号通路对转化生长因子依赖的Lefty上调的影响。加入K-ras小干扰RNA、MEK抑制剂U0126或细胞外信号调节蛋白激酶(ERK)抑制剂LY294002，检测Ras/MEK/ERK通路对转化生长因子-β介导的Lefty上调的影响。结果：在7株细胞中，有6株TGFRβ上调Lefty信使RNA水平。Lefty对促进肿瘤的分子Nodal发挥拮抗作用，因为重组Lefty抑制了Nodal介导的增殖。有趣的是，抑制RAS/MEK/ERK通路显著增强了转化生长因子介导的Lefty上调，提示RAS/MEK/ERK信号通路抑制了转化生长因子-β-左旋体途径。结论：左旋体是一种新的介导胰腺癌细胞生长抑制的转化生长因子-β靶分子。此外，RAS/MEK/ERK通路的激活是胰腺癌通过转化生长因子-β-左轴逃避生长抑制的一种机制。这些结果提示了一种新的治疗胰腺癌的策略，即联合应用RAS/MEK/ERK抑制剂和转化生长因子-β。
Objectives: The objectives of the present study were (i) to identify a novel tumor suppressor gene whose expression level was regulated by transforming growth factor (TGF-beta) and (ii) to evaluate the effect of Ras/MEK/ERK signaling on TGF-beta-dependent Lefty up-regulation.Methods: Human pancreatic cancer cell lines were used. The effect of Ras/MEK/ERK pathway on TGF-beta-mediated Lefty up-regulation was tested by adding K-ras small interfering RNA, MEK inhibitor U0126, or extracellular signalYregulated kinase (ERK) inhibitor LY294002.Results: Transforming growth factor beta upregulated Lefty messenger RNA levels within 6 of the 7 cell lines. Lefty exerts an antagonistic effect against the tumor-promoting molecule, Nodal, as recombinant Lefty suppressed Nodal-mediated proliferation. Interestingly, inhibition of the Ras/MEK/ERK pathway dramatically enhanced TGF-mediated Lefty up-regulation, suggesting that Ras/MEK/ERK signaling suppresses TGF-beta-Lefty pathway.Conclusions: Our data suggest that Lefty is a novel TGF-beta target molecule that mediates growth inhibition of pancreatic cancer cells. In addition, activation of the Ras/MEK/ERK pathway serves as a mechanism by which pancreatic cancer escapes from growth inhibition by the TGF-beta-Lefty axis. The results imply a novel therapeutic strategy for pancreatic cancer, that is, combination treatment with Ras/MEK/ERK inhibitors and TGF-beta.