研究表明，Disabled-2（Dab2）能通过在细胞浆内稳定Axin蛋白，发挥抑制Wnt信号通路的作用。我们发现Dab2在肺癌中表达减少并存在启动子甲基化，其表达和甲基化水平与肺癌进展有关，而且发现Dab2虽然不含入核序列，却能入核并与Axin协同表达，但其入核机制及在细胞核内的功能尚不清楚。我们推测Dab2的低表达与甲基化有关；Dab2可能是在Axin的协助下入核，并以Dab2-Axin复合体的形式在细胞核内拮抗beta-cat，发挥抑制Wnt通路活性的作用。本研究拟通过双向调控甲基转移酶活性明确Dab2甲基化水平与其蛋白表达的关系；双向调控Dab2和Axin的表达，构建Dab2与Axin、Axin与beta-cat结合能力不同，及Axin出入核能力不同的突变体，并结合莱普霉素B阻断Axin出核等方法，阐明Dab2入核机制及其在细胞核内抑制Wnt通路活性和肺癌细胞增殖、侵袭的分子机制。

It is reported that Disabled-2 (Dab2) can stabilize Axin protein in the cytoplasm and inhibit the Wnt signaling pathway. We found the reduced expression and promoter methylation of Dab2 in lung cancers,which were correlated with the development of lung cancers. We observed that Dab2, which did not contain the nuclear location sequence, could enter into the nucleus and co-localization with Axin. But the mechanism of Dab2 entering into the nucleus and the function of Dab2 in nucleus are unclear. We speculate that the reduction of Dab2 may relate to the methylation of Dab2 gene. Dab2 may enter into cell nucleus under the assistance of Axin, and form Dab2-Axin complex to antagonize beta-catenin and inhibit the activation of Wnt pathway. This study plan to: bidirectional regulate the activity of methyltransferase, and reveal the correlations among methylation, Dab2 or Axin expression; bidirectional regulate the expression of Dab2 and/or Axin, and construct mutants of Dab2 and Axin genes, including the mutants have different binding capacity and the mutants have different capacity of entering or exporting the nucleus,along with the application of Leptomycin B (blocking the nuclear export signaling), then investigate the molecular mechanisms of Dab2 entering into cell nucleus and inhibiting the activation of Wnt pathway and the proliferation and invasion of lung cancers.