HNF4α is a therapeutic target that links AMPK to WNT signaling in early-stage gastric cancer

Background Worldwide, gastric cancer 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. Objective To determine oncogenic mechanisms and novel therapeutic targets specific for gastric cancer by identifying commonly dys-regulated genes from the tumors of both Asian-Pacific and Caucasian patients. Design We generated transcriptomic profiles of 22 Caucasian gastric cancer tumors and their matched non-cancerous samples, and performed an integrative analysis across different gastric cancer gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signaling pathways by RNAi and/or pharmacologic inhibition. Results We found that HNF4α upregulation was a key signaling event in gastric tumors from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumor cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signaling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest, and tumor growth inhibition. HNF4α also regulated WNT signaling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumors. Conclusions Our results indicate that HNF4α is a targetable oncoprotein in gastric cancer, is regulated by AMPK signaling through AMPKα, and resides upstream of WNT signaling. HNF4α may regulate “metabolic switch” characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signaling cascade represents a potentially targetable pathway for drug development. Integrative analysis of Caucasian and Asian-Pacific gastric tumor expression datasets (including newly generated transcriptomic profiling of 22 tumors in this study) revealed a relatively small common sets of highly overexpressed genes.

背景 胃癌在全球范围内为第四大常见恶性肿瘤，同时也是东亚地区最高发的癌症。针对该病的靶向治疗研发曾聚焦于少数已知致癌基因，但临床疗效有限。
目的 本研究通过分析亚太裔与高加索裔胃癌患者肿瘤组织中共同失调的基因，旨在阐明胃癌特异性致癌机制，并发掘全新治疗靶点。
设计 我们对22例高加索裔胃癌组织及其配对的癌旁正常样本进行了转录组表达谱（transcriptomic profile）检测，并整合分析了多套胃癌基因表达数据集。同时采用RNA干扰（RNAi）及/或药物抑制手段，对常见高表达致癌基因及其参与的信号通路的抑制效应进行了验证。
结果 研究发现，肝细胞核因子4α（HNF4α）的上调是高加索裔与亚裔胃癌组织中的关键信号事件，且拮抗HNF4α可发挥抗肿瘤活性。胃癌（GC）细胞系及异种移植模型中的功能扰动实验进一步证实，AMP活化蛋白激酶α（AMPKα）信号通路与AMPK激动剂二甲双胍可下调HNF4α的表达；阻断HNF4α活性可导致细胞周期蛋白表达下调、细胞周期阻滞及肿瘤生长受抑。此外，HNF4α还通过其靶基因WNT5A调控WNT信号通路，而WNT5A是弥漫型胃癌的潜在预后标志物。
结论 本研究结果表明，HNF4α是胃癌中可靶向的癌蛋白，其通过AMPKα介导的AMPK信号通路受到调控，且位于WNT信号通路的上游。HNF4α可能调控恶性表型共有的“代谢转换”特征，其靶基因WNT5A亦具备潜在预后价值。AMPKα-HNF4α-WNT5A信号级联反应为抗肿瘤药物研发提供了潜在可靶向的通路。对高加索裔与亚太地区胃癌组织表达数据集（包含本研究新生成的22例样本的转录组表达谱）的整合分析显示，共同高表达的基因集规模相对有限。