Direct regulation of FOXK1 by C-jun promotes proliferation, invasion and metastasis in gastric cancer cells.
Direct regulation of FOXK1 by C-jun promotes proliferation, invasion and metastasis in gastric cancer cells.
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C-JUN对FOXK1的直接调节促进了胃癌细胞中的增殖，侵袭和转移。
DOI：
10.1038/cddis.2016.225
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发表时间：
2016-11-24
影响因子：
9
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Peng Y;Zhang P;Huang X;Yan Q;Wu M;Xie R;Wu Y;Zhang M;Nan Q;Zhao J;Li A;Xiong J;Ren Y;Bai Y;Chen Y;Liu S;Wang J
Forkhead box(Fox)K1是Fox转录因子超家族的成员。FOXK1的高表达与多种癌症有关。然而，FOXK1的表达是否与胃癌的发生和发展有关尚不清楚。我们利用Promo软件对FOXK1启动子进行了分析，发现了包括c-jun在内的几个结合序列转录因子。然而，FOXK1影响c-jun介导的恶性表型的分子机制尚不清楚。在此，我们发现FOXK1蛋白在8/10(80.0%)新鲜癌组织中的表达高于癌旁正常组织。FOXK1过表达促进了GC细胞的增殖、迁移和侵袭。此外，转化生长因子-β-1(转化生长因子-β-1)可刺激FOXK1的表达。FOXK1作为一种潜在的上皮向间充质转化(EMT)诱导剂，在稳定的FOXK1细胞中通过刺激波形蛋白的表达和诱导E-钙粘附素的丢失而发挥作用。启动子报告和染色质免疫沉淀实验结果表明，c-jun直接与人FOXK1基因启动子结合并激活。FOXK1和c-jun在胃癌细胞和组织中的表达呈正相关。FOXK1和c-jun的表达与肿瘤进展相关，是预测GC患者总生存期的重要指标。然而，siRNA介导的c-jun在FOXK1过表达细胞中的抑制逆转了EMT，以及增殖和转移的表型。在体内，c-jun通过原位移植促进FOXK1介导的增殖和转移。这些证据表明，FOXK1介导的c-jun调控促进了人类GC的发生和发展。
Forkhead box (FOX) K1 is a member of the FOX transcription factor superfamily. High FOXK1 expression is associated with several cancers. However, whether FOXK1 expression contributes to gastric cancer (GC) development and progression remains unknown. We analyzed the FOXK1 promoter using the Promo software and found several binding sequence transcription factors, including c-jun. However, the molecular mechanism by which FOXK1 affects the c-jun-mediated malignant phenotype is poorly understood. Here, we found that FOXK1 protein expression was higher in 8/10 (80.0%) fresh cancer tissues compared with that in adjacent normal tissues. FOXK1 overexpression enhanced the proliferation, migration and invasion of GC cells. Moreover, FOXK1 expression was stimulated by transforming growth factor-β1 (TGF-β1). FOXK1 acted as a potential epithelial-to-mesenchymal transition (EMT) inducer by stimulating vimentin expression and inducing the loss of E-cadherin in stable FOXK1-transfected cells. The results of promoter reporter and chromatin immunoprecipitation assays demonstrated that c-jun directly binds to and activates the human FOXK1 gene promoter. A positive correlation was observed between the expression patterns of FOXK1 and c-jun in GC cells and tissue. FOXK1 and c-jun expression were correlated with tumor progression and represented significant predictors of overall survival in GC patients. However, the siRNA-mediated repression of c-jun in FOXK1-overexpressing cells reversed EMT, as well as the proliferative and metastatic phenotypes. In vivo, c-jun promoted FOXK1-mediated proliferation and metastasis via orthotopic implantation. The evidence presented here suggests that FOXK1-directed regulation by c-jun promote the development and progression of human GC.