HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer.
HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer.
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DOI：
10.1136/gutjnl-2014-307918
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发表时间：
2016-01
期刊：
影响因子：
24.5
通讯作者：
Kim YH
中科院分区：
文献类型：
--
作者：
Chang HR;Nam S;Kook MC;Kim KT;Liu X;Yao H;Jung HR;Lemos R Jr;Seo HH;Park HS;Gim Y;Hong D;Huh I;Kim YW;Tan D;Liu CG;Powis G;Park T;Liang H;Kim YH
胃癌（gastric cancer，GC）是世界范围内第四大常见恶性肿瘤，也是东亚地区最常见的癌症。针对这种疾病的靶向治疗的发展集中在一些已知的致癌基因上，但效果有限。通过鉴定亚太和高加索患者肿瘤中常见的失调基因，确定GC的致癌机制和新的特异性治疗靶点。我们生成了22个高加索人GC肿瘤及其匹配的非癌样本的转录组学谱，并在不同的GC基因表达数据集上进行了综合分析。我们研究了通过RNAi和/或药理学抑制来抑制通常过表达的癌基因及其组成信号通路。肝细胞核因子-4 α（HNF 4 α）上调是高加索人和亚洲人胃肿瘤中的关键信号事件，HNF 4 α拮抗作用无效。GC肿瘤细胞系和异种移植模型中的扰动实验进一步证明，AMPKα信号传导和AMPK激动剂二甲双胍下调HNF 4 α;阻断HNF 4 α活性导致细胞周期蛋白下调、细胞周期停滞和肿瘤生长抑制。HNF 4 α还通过其靶基因WNT 5A调节WNT信号传导，WNT 5A是弥漫型胃肿瘤的潜在预后标志物。我们的研究结果表明，HNF 4 α是GC中的靶向癌蛋白，通过AMPK α受AMPK信号调节，并位于WNT信号的上游。HNF 4 α可能调节一般恶性表型的“代谢开关”特征，其靶点WNT 5A具有潜在的预后价值。AMPKα-HNF 4 α-WNT 5A信号级联是药物开发的潜在靶向途径。
Worldwide, gastric cancer (GC) is the fourth most common malignancy and the most common cancer in East Asia. Development of targeted therapies for this disease has focused on a few known oncogenes but has had limited effects. To determine oncogenic mechanisms and novel therapeutic targets specific for GC by identifying commonly dysregulated genes from the tumours of both Asian-Pacific and Caucasian patients. We generated transcriptomic profiles of 22 Caucasian GC tumours and their matched non-cancerous samples and performed an integrative analysis across different GC gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signalling pathways by RNAi and/or pharmacological inhibition. Hepatocyte nuclear factor-4α (HNF4α) upregulation was a key signalling event in gastric tumours from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumour cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signalling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest and tumour growth inhibition. HNF4α also regulated WNT signalling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumours. Our results indicate that HNF4α is a targetable oncoprotein in GC, is regulated by AMPK signalling through AMPKα and resides upstream of WNT signalling. HNF4α may regulate ‘metabolic switch’ characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signalling cascade represents a potentially targetable pathway for drug development.