A role for human MUC4 mucin gene, the ErbB2 ligand, as a target of TGF-β in pancreatic carcinogenesis
A role for human MUC4 mucin gene, the ErbB2 ligand, as a target of TGF-β in pancreatic carcinogenesis
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DOI：
10.1038/sj.onc.1207769
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发表时间：
2004-07-29
期刊：
影响因子：
8
通讯作者：
Van Seuningen, I
中科院分区：
文献类型：
--
作者：
Jonckheere, N;Perrais, M;Van Seuningen, I
MUC4编码一种在胰腺癌中过度表达的大跨膜粘蛋白。导致这种表达模式改变的分子机制尚不清楚。转化生长因子-β是一种多效性细胞因子，通过激活Smads蛋白调节多种参与胰腺癌发生的基因，而MUC4启动子中含有丰富的Smad结合元件。我们的目的是研究转化生长因子-β对胰腺癌细胞MUC4表达的调节是否严格依赖于Smad4的活性。三种胰腺癌细胞系CAPAN-1(MUC4+/Smad4-)、CAPAN-2(MUC4+/Smad4+)和Panc-1(MUC4-/Smad4+)。RT-PCR、转染实验和免疫组织化学结果显示：(1)Smad4和Smad4的表达均受转化生长因子-β的上调，(2)Smad2与Smad4正向协同激活启动子，(3)外源性转化生长因子-β激活Smad4可诱导Smad4与启动子结合，(4)Smad7和c-ski均抑制Smad4的激活。当Smad4突变和失活时，转化生长因子-β通过MAPK、PI3K和PKA信号通路激活MUC4的表达。在PANC-1细胞中没有表达是由于历史上的脱乙酰基。综上所述，这些结果表明，转化生长因子-β上调MUC4仅限于高分化的胰腺癌细胞，并指出转化生长因子-β作为关键分子在胰腺癌中靶向MUC4过度表达的新机制。
MUC4 encodes a large transmembrane mucin that is overexpressed in pancreatic adenocarcinomas. The molecular mechanisms responsible for that altered pattern of expression are unknown. TGF-beta, a pleiotropic cytokine, regulates numerous genes involved in pancreatic carcinogenesis via activation of the Smads proteins and MUC4 promoter is rich in Smad-binding elements. Our aim was to study whether the regulation of MUC4 expression by TGF-beta in pancreatic cancer cells was strictly dependent on Smad4 activity. Three pancreatic cancer cell lines, CAPAN-1 (MUC4 + /Smad4-), CAPAN-2 (MUC4 + /Smad4+) and PANC-1 (MUC4-/Smad4 +), were used. By RT-PCR, transfection assays and immunohistochemistry, we show that (i) both MUC4 mRNA and apomucin expression are upregulated by TGF-beta, (ii) Smad2 positively cooperates with Smad4 to activate the promoter, (iii) activation of Smad4 by exogenous TGF-beta induces Smad4 binding to the promoter, (iv) Smad7 and c-ski both inhibit activation by Smad4. When Smad4 is mutated and inactive, TGF-beta activates MUC4 expression via MAPK, PI3K and PKA signaling pathways. Absence of expression in PANC-1 cells is due to historic deacetylation. Altogether, these results indicate that upregulation of MUC4 by TGF-beta is restricted to well-differentiated pancreatic cancer cells, and point out a novel mechanism for TGF-beta as a key molecule in targeting MUC4 overexpression in pancreatic adenocarcinomas.