GATA6 activates Wnt signaling in pancreatic cancer by negatively regulating the Wnt antagonist Dickkopf-1.
GATA6 activates Wnt signaling in pancreatic cancer by negatively regulating the Wnt antagonist Dickkopf-1.
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DOI：
10.1371/journal.pone.0022129
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Iacobuzio-Donahue CA
中科院分区：
文献类型：
--
作者：
Zhong Y;Wang Z;Fu B;Pan F;Yachida S;Dhara M;Albesiano E;Li L;Naito Y;Vilardell F;Cummings C;Martinelli P;Li A;Yonescu R;Ma Q;Griffin CA;Real FX;Iacobuzio-Donahue CA
胰腺导管腺癌（PDAC）是一种高致死性疾病，其特点是诊断晚，治疗耐药。与发育细胞信号传导途径的扰动相关的确定基因中的复发性遗传改变与PDAC的发展和进展相关。在这里，我们表明，GATA 6有助于胰腺上皮内瘤形成的时间进展过程中，凭借Wnt通路激活胰腺癌的发生。GATA 6通过定量PCR和荧光原位杂交在人胰腺上皮内瘤变和PDAC组织中反复扩增，并且GATA 6拷贝数与患者的总体生存率显著相关。癌细胞系中GATA 6的强制过表达增强了体外软琼脂中的细胞增殖和集落形成以及体内生长，以及增加了Wnt信号传导。相比之下，siRNA介导的GATA 6敲低导致这些相同参数的相应降低。发现GATA 6的作用是由于其结合DNA的能力，因为GATA 6的DNA结合突变体的强制过表达在体外或体内对细胞生长没有影响，它们也不影响这些相同细胞中的Wnt信号传导水平。微阵列分析揭示了Wnt拮抗剂Dickopf-1（DKK 1）作为一个与GATA 6敲低相关的失调基因，并通过染色质免疫沉淀和电泳迁移率变动分析证实了GATA 6与DKK 1启动子的直接结合。瞬时转染GATA 6，而不是突变体GATA 6，进入癌细胞系导致DKK 1 mRNA表达和DKK 1蛋白分泌到培养基中的减少。DKK 1的强制过表达拮抗GATA 6对胰腺癌细胞中Wnt信号传导的影响。这些发现说明GATA 6促进胰腺癌发生的一种机制是凭借其通过调节DKK 1激活经典Wnt信号传导。
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by late diagnosis and treatment resistance. Recurrent genetic alterations in defined genes in association with perturbations of developmental cell signaling pathways have been associated with PDAC development and progression. Here, we show that GATA6 contributes to pancreatic carcinogenesis during the temporal progression of pancreatic intraepithelial neoplasia by virtue of Wnt pathway activation. GATA6 is recurrently amplified by both quantitative-PCR and fluorescent in-situ hybridization in human pancreatic intraepithelial neoplasia and in PDAC tissues, and GATA6 copy number is significantly correlated with overall patient survival. Forced overexpression of GATA6 in cancer cell lines enhanced cell proliferation and colony formation in soft agar in vitro and growth in vivo, as well as increased Wnt signaling. By contrast siRNA mediated knockdown of GATA6 led to corresponding decreases in these same parameters. The effects of GATA6 were found to be due to its ability to bind DNA, as forced overexpression of a DNA-binding mutant of GATA6 had no effects on cell growth in vitro or in vivo, nor did they affect Wnt signaling levels in these same cells. A microarray analysis revealed the Wnt antagonist Dickopf-1 (DKK1) as a dysregulated gene in association with GATA6 knockdown, and direct binding of GATA6 to the DKK1 promoter was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift assays. Transient transfection of GATA6, but not mutant GATA6, into cancer cell lines led to decreased DKK1 mRNA expression and secretion of DKK1 protein into culture media. Forced overexpression of DKK1 antagonized the effects of GATA6 on Wnt signaling in pancreatic cancer cells. These findings illustrate that one mechanism by which GATA6 promotes pancreatic carcinogenesis is by virtue of its activation of canonical Wnt signaling via regulation of DKK1.
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DOI：
10.1016/s0167-4781(00)00013-0
发表时间：
2000-02-29
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION
影响因子：
--
作者：
Al-azzeh, ED;Fegert, P;Gött, P
通讯作者：
Gött, P
影响因子：
2.4
作者：
Haveri H;Westerholm-Ormio M;Lindfors K;Mäki M;Savilahti E;Andersson LC;Heikinheimo M
通讯作者：
Heikinheimo M
影响因子：
3.7
作者：
Pasca di Magliano M;Biankin AV;Heiser PW;Cano DA;Gutierrez PJ;Deramaudt T;Segara D;Dawson AC;Kench JG;Henshall SM;Sutherland RL;Dlugosz A;Rustgi AK;Hebrok M
通讯作者：
Hebrok M
影响因子：
4.5
作者：
Kwei KA;Bashyam MD;Kao J;Ratheesh R;Reddy EC;Kim YH;Montgomery K;Giacomini CP;Choi YL;Chatterjee S;Karikari CA;Salari K;Wang P;Hernandez-Boussard T;Swarnalata G;van de Rijn M;Maitra A;Pollack JR
通讯作者：
Pollack JR
影响因子：
5.8
作者：
Laitinen, MPE;Anttonen, M;Heikinheimo, M
通讯作者：
Heikinheimo, M