Trans-acting Nonsynonymous Variant of FOXA1 Predisposes to Hepatocellular Carcinoma Through Modulating FOXA1-ERα Transcriptional Program and May Have Undergone Natural Selection
Trans-acting Nonsynonymous Variant of FOXA1 Predisposes to Hepatocellular Carcinoma Through Modulating FOXA1-ERα Transcriptional Program and May Have Undergone Natural Selection
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FOXA1 的反式作用非同义变体通过调节 FOXA1-ERα 转录程序易患肝细胞癌，并且可能经历了自然选择
DOI：
10.1093/carcin/bgz136
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发表时间：
2019
期刊：
影响因子：
4.7
通讯作者：
Wang Haijian
中科院分区：
文献类型：
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作者：
Wang Sheng;Xiang Chan;Mou Lin;Yang Yuan;Zhong Rong;Wang Liyan;Sun Chang;Qin Zhaoyu;Yang Jingmin;Qian Ji;Zhao Yuanyuan;Wang Yi;Pan Xuedong;Qie Jingbo;Jiang Yan;Wang Xiaofeng;Yang Yajun;Zhou Weiping;Miao Xiaoping;He Fuchu;Jin Li;Wang Haijian
先锋转录因子叉头盒A1 （FOXA1）和雌激素受体的相互作用与肝细胞癌（HCC）的性别二态性有关，但其多态性的病因学相关性尚不清楚。在病例对照研究（1152例患者与1242例对照）中，我们观察到与含有ala83基因型的非同义Thr83Ala变体ofFOXA1相关的乙型肝炎病毒携带者的HCC易感性显著增加（优势比[OR]， 1.28； 95%置信区间[CI]， 1.11−1.48，在独立人群中验证，933例患者与1030例对照），其启动子处的紧密连锁（CGC）5/6or7重复多态性(OR 1.32；（CGC）6or7-repeat-containing基因型95% CI 1.10-1.60)，以及它们的组合单倍型（OR 1.50; (CGC)6or7- Ala83单倍型95% CI 1.24-1.81）。易感基因FOXA1-Ala83削弱了其与ERα的相互作用，减弱了其对某些双靶基因（如1型碘甲状腺原氨酸脱碘酶、UDP葡萄糖醛基转移酶2家族、多肽B17和钠/牛磺胆酸共转运多肽）的转激活，但在HCC患者中与α-胎蛋白（AFP）细胞表达增强和AFP血清浓度升高相关（n= 1096）。带有（CGC）6or7repeat的foxa1易感顺式变异增强了与转录因子早期生长反应1的结合，增强了启动子活性和基因表达。种群进化遗传学分析表明，FOXA1-Thr83具有显著的种群分化和独特的单倍型结构，表明其可能在中国种群中经历了正自然选择。这些发现在流行病学上强调了FOXA1-ERα转录程序和调控网络在肝癌发生中的功能意义。
Interplay of pioneer transcription factor forkhead box A1 (FOXA1) and estrogen receptor has been implicated in sexual dimorphism in hepatocellular carcinoma (HCC), but etiological relevance of its polymorphism was unknown. In the case control study (1152 patients versus1242 controls), we observed significant increase in HCC susceptibility in hepatitis B virus carriers associated with a non-synonymous Thr83Ala variant ofFOXA1(odds ratio [OR], 1.28; 95% confidence interval [CI], 1.11−1.48, for Ala83-containing genotype, after validation in an independent population with 933 patients versus 1030 controls), a tightly linked (CGC)5/6or7repeat polymorphism at its promoter (OR 1.32; 95% CI 1.10–1.60, for (CGC)6or7-repeat-containing genotype), and their combined haplotype (OR 1.50; 95% CI 1.24–1.81, for (CGC)6or7−Ala83 haplotype). The susceptible FOXA1-Ala83 impairs its interaction with ERα, attenuates transactivation toward some of their dual target genes, such as type 1 iodothyronine deiodinase, UDP glucuronosyltransferase 2 family, polypeptide B17 and sodium/taurocholate cotransporting polypeptide, but correlates with strengthened cellular expression of α-fetoprotein (AFP) and elevated AFP serum concentration in HCC patients (n= 1096). The susceptibleFOXA1 cis-variant with (CGC)6or7repeat strengthens the binding to transcription factor early growth response 1 and enhances promoter activity and gene expression. Evolutionary population genetics analyses with public datasets reveal significant population differentiation and unique haplotype structure of the derived protective FOXA1-Thr83 and suggest that it may have undergone positive natural selection in Chinese population. These findings epidemiologically highlight the functional significance of FOXA1-ERα transcriptional program and regulatory network in liver cancer development.