State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences; Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Carcinogenesis. 2020 Apr 22;41(2):146-158. doi: 10.1093/carcin/bgz136.
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 of FOXA1 (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)5/6or7 repeat 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 susceptible FOXA1 cis-variant with (CGC)6or7 repeat 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.
叉头框转录因子 A1（FOXA1）与雌激素受体的相互作用已被认为与肝癌（HCC）的性别二态性有关，但该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，我们观察到乙型肝炎病毒携带者中 HCC 易感性显著增加，与 FOXA1 的非 synonymous Thr83Ala 变体相关（比值比[OR]，1.28；95%置信区间[CI]，1.11-1.48，对于包含 Ala83 的基因型，在包含 933 例患者和 1030 例对照的独立人群中验证后），其启动子处紧密连锁的（CGC）5/6 或 7 重复多态性（OR 1.32；95%CI 1.10-1.60，对于包含（CGC）6 或 7-重复的基因型），以及它们的组合单倍型（OR 1.50；95%CI 1.24-1.81，对于（CGC）6 或 7-Ala83 单倍型）。易感的 FOXA1-Ala83 会损害其与 ERα 的相互作用，减弱对某些双重靶基因（如 1 型甲状腺素脱碘酶、UDP 葡萄糖醛酸基转移酶 2 家族、多肽 B17 和牛磺酸胆酸钠共转运蛋白）的转录激活，但与 HCC 患者（n=1096）中α-胎蛋白（AFP）的细胞表达增强和 AFP 血清浓度升高相关。具有（CGC）6 或 7 重复的易感 FOXA1 顺式变体增强了与转录因子早期生长反应 1 的结合，并增强了启动子活性和基因表达。使用公共数据集进行的进化群体遗传学分析显示，衍生的保护性 FOXA1-Thr83 存在显著的群体分化和独特的单倍型结构，并表明它可能在中国人群中经历了正向自然选择。这些发现从流行病学角度强调了 FOXA1-ERα 转录程序和调控网络在肝癌发展中的功能意义。
