转录因子HEY2通过调控TGF-β/Smads通路促进肝癌发生发展的研究

TGF-β is a pleiotropic factor. It exerts tumor-suppressive effects in the premalignant stage of tumor, while in the advanced stage, TGF-β signaling turns into promoting tumor growth and invasion. Any disruption in TGF-β signaling pathway will result in tumor development and progression. HEY2 encodes a protein which exercises the function of transcriptional repression and its expression is induced by Notch signaling pathway. It has been reported that HEY2 plays an important role in embryonic development and cardiovascular development, and it is up-regulated in osteosarcoma. During the previous study, we found that HEY2 is a negative regulator of TGF-β signaling pathway. HEY2 could form a complex with Smad3/Smad4 and reverse the TGF-β inhibition on downstream target gene c-Myc. Besides, HEY2 protein was shown to be highly up-regulated in HCC tissues, which suggested that it may be related with HCC development. In this proposal, we will study deeply about :1) The mechanism of HEY2 in regulating the TGF-β/Smads signaling pathway and the downstream target expression; 2) HEY2’s role in cell cycle, proliferation, migration and its tumorigenicity ability in nude mice; 3) The difference of HEY2 expression and distribution between HCC tissue and the adjacent tissue, and the association of these differences with the clinical phenotypes. Finally, we will determine the value of HEY2 as a molecular marker for HCC diagnosis.

TGF-β是一个多效因子,在肿瘤发生的起始阶段起生长抑制作用，在进展期和晚期转而呈现促进肿瘤细胞生长和转移的作用，该信号通路紊乱是导致肿瘤发生发展的重要因素之一。转录因子HEY2编码的蛋白行使转录抑制功能,是Notch 通路的效应基因；HEY2在胚胎发育、心血管发生中具重要作用，在骨肉瘤中上调表达。本研究团队在前期研究中发现，HEY2是一个新的TGF-β/Smads信号通路负调控因子，能够和TGF-β通路重要传导蛋白Smad3/4互作并阻碍TGF-β对下游靶基因c-Myc 的抑制，此外HEY2在肝癌组织中上调表达，提示HEY2在肝癌发生发展中具有一定作用。本项目将继续研究HEY2对TGF-β/Smads信号通路及下游靶蛋白的分子调控机制，HEY2对肝癌细胞周期、增殖、转移和裸鼠成瘤能力的影响以及HEY2在肝癌组织中的表达、分布差异及与临床病理特征相关性，最终探讨其作为肝癌分子标志物的价值。

转化生长因子β（TGF-β）通路的功能障碍在肝细胞癌（HCC）发生发展过程中发挥重要作用。在本研究中，我们的研究结果表明了HEY2通过影响TGF-β信号通路在肝癌发生发展过程中发挥作用。HEY2在肝癌中表达增高，且组织芯片结果显示其在肝癌细胞质中的表达增高与肝癌患者较差的预后显著相关。HEY2异常高表达会阻止TGF-β诱导的肝癌细胞生长抑制作用，同时阻止TGF-β引起的效应基因c-myc的表达下调。相应地相反方向的研究结果表明，在肝癌细胞中干扰掉HEY2会促进TGF-β介导的肝癌细胞的生物学反应及c-myc下调作用。进一步我们研究了HEY2发挥生物学功能的分子机制，HEY2可以与TGF-β信号通路中主要转导成员Smad3和Smad4 形成复合物并抑制Smad3/Smad4的转录活性，进而影响TGF-β信号通路。综上所述，我们阐述了HEY2通过阻滞TGF-β的肿瘤抑制作用从而促进肝癌发生发展的作用。TGF-β的肿瘤抑制作用向肿瘤促进作用的转变是肿瘤发生的关键问题之一，我们的结果为TGF-β作用的转换机制提出了一个新的参考。