EBP1促进FOXA1抑制PI3K/AKT通路介导表观遗传改变影响肝细胞癌侵袭转移的研究

FOXA1在不同的肿瘤可能发挥抑癌或促癌的作用，而在肝细胞癌中未见报道。前期研究表明，FOXA1能抑制肝细胞癌增殖、侵袭及转移，而该作用受EBP1剪切体p42调控；其机制可能与EBP1 p42结合FOXA1共同抑制PI3K/AKT通路活性有关；此外，我们还发现FOXA1抑制PI3K/AKT通路后能调节EZH2活性，发挥表观遗传调控作用影响肝癌细胞侵袭转移。本项目进一步研究如下：1）在肝细胞癌中验证FOXA1的抑癌功能受EBP1 p42的调控；2）明确EBP1 p42促进FOXA1抑制PIK3R1转录从而下调PI3K/AKT通路活性的机制；3）明确FOXA1可以通过PI3K/AKT通路影响EZH2磷酸化从而影响其甲基化转移酶活性；4）探讨FOXA1调控EZH2导致基因表观遗传学改变在抑制肝癌侵袭、转移中的作用。本研究将为肝癌的发病机理提供新内容，为寻求肝癌新的分子靶点提供理论依据。

FOXA1 exhibiting a dual role, tumor suppression or promoting, depends on different tumors, but its role in hepatocellular carcinoma remains unclear. Our previous study showed that FOXA1 inhibits hepatocellular carcinoma proliferation, migration, and invasion regulated by EBP1 alternatively spliced isoform p42. The mechanism research showed that EBP1 p42 combined with FOXA1 may exert tumor suppressing role through blocking PI3K/AKT signal activity. In addition, we found FOXA1 may mediate EZH2 activity to induce epigenetic regulation of gene expression through down-regulating PI3K/AKT signal activity in hepatocellular carcinoma. Further studies will be performed as follow: 1) Confirming the tumor suppressing role of FOXA1 regulated by EBP1 p42 in hepatocellular carcinoma; 2) Validating EBP1 p42 promoting FOXA1 to inhibit PI3K/AKT signal activity by suppressing transcription of PIK3R1; 3) Confirming FOXA1 mediating EZH2’s phosphorylation through PI3K/AKT pathway; 4) Discussing the tumor suppression role of FOXA1 mediating EZH2 on epigenetic regulating gene expression in hepatocellular carcinoma. This program will provide a better understanding of liver cancer pathogenesis and a new potential target for treatment.