LisH2在经典Wnt信号转导通路中的作用及其分子机制研究

Canonical Wnt signaling pathway has been well established to be a key regulator of embryonic development. It is reported that disorders in this pathway contributes to the pathogenesis of colorectal cancer and other malignant tumors. Nuclear translocation of β-catenin to activate target genes expression is one of the key events in canonical Wnt pathway. However, the underlying molecular mechanism that controls β-catenin nuclear accumulation remains poorly understood. Here, we find that LisH2, a protein containing LisH (Lissencephaly 1 homology) domain, may be involved in modulating the nuclear accumulation of β-catenin. Our results show that depletion of LisH2 suppresses Wnt-induced reporter activation, target genes expression and β-catenin nuclear accumulation, causes ventralization of zebrafish embryos, and inhibits tumorigenicity of colorectal cancer cells. These data indicate that LisH2 may regulate canonical Wnt pathway by facilitating β-catenin nuclear localization, which plays an important role in embryonic development and colorectal tumorigenesis. In this proposal, we will systematically characterize the biological function and the underlying mechanism of LisH2 in canonical Wnt pathway at the molecular, cellular, animal and clinical levels. This study will provide novel potential therapeutic targets for human diseases related to the dysfunction of canonical Wnt pathway.

经典Wnt信号通路参与动物胚胎发育过程，其功能异常与结直肠癌等恶性肿瘤密切相关。β-catenin进入细胞核激活靶基因的表达是经典Wnt信号通路的关键事件之一，但有关β-catenin核内累积的调控机理至今仍知之甚少。我们发现无脑回综合征致病基因Lissencephaly 1的相关蛋白LisH2（Lis1 Homology 2）可能参与其中。我们前期研究显示下调LisH2不仅可抑制Wnt信号诱导的报告基因活性、靶基因表达和β-catenin核内累积，而且还导致斑马鱼胚胎发育腹部化，抑制结直肠癌细胞的成瘤能力。这些结果提示，LisH2可能通过调节β-catenin核内累积而影响经典Wnt信号通路，进而调控胚胎发育和结直肠癌发病过程。本项目拟在分子、细胞、动物和临床水平，系统研究LisH2在经典Wnt信号通路中的作用及其分子调控机制，为与Wnt信号通路异常相关的疾病提供新的潜在治疗线索。

β-catenin在细胞核内的累积是经典Wnt信号通路激活的关键事件之一。然而，有关β-catenin核内累积的分子调控机制迄今仍知之甚少。我们的研究发现LisH2（Lis1 Homology 2，又称Twa1，Two hybrid associated protein No. 1 with RanBPM）的mRNA 在结直肠癌组织中表达明显上调，提示其可能参与结直肠癌的发生发展。另外，我们发现LisH2通过促进β-catenin在细胞核中的累积，参与调节经典Wnt信号通路，进而调控胚胎早期背腹体轴发育以及结直肠癌的发生和发展。这一研究有助于我们深入了解LisH2的生物学功能和经典Wnt信号通路的分子调控机理，为与该信号通路异常相关的人类疾病提供新的潜在治疗靶点。