ALK介导DAB2IP抑制乳腺癌侵袭性伪足的功能与分子机制研究

Invadopodia plays an important role in breast cancer metastasis. Our previous research has showed that DAB2IP can inhibit the formation of invadopodia by regulating phosphorylation of Cortactin(Y421) in breast cancer, while the mechanism is stll unclear. We screened out a new molecule ALK through protein kinase chip assay. Lately, we have found that the ALK could combine with Cortactin, and DAB2IP could inhibit the formatin of this complex . Knocking-down ALK expression could reverse the facilitative effect of invadopodia induced by loss of DAB2IP. Thus, we supposed that ALK could mediate the inhibition of invadopodia by DAB2IP and suppress the metastasis of breast cancer. Our project aims to:1. Prove that DAB2IP negatively regulate ALK; 2. Uncover the mechanism of ALK regulating Cortactin phosphorylation; 3.Clatify that ALK could mediate the inhibition of invadopodia by DAB2IP;4. Aanalyse the relationship beween the expression of DAB2IP, ALK with the recurrence and metastasis of breast cancer based in biological samples library. Thus, we try to illustrate the function and mechanism that ALK could mediate the inhibition of invadopodia by DAB2IP, and possibly show a molecular target for preventing breast cancer metastasis.

侵袭性伪足在乳腺癌转移中具有重要作用。我们前期的研究证实DAB2IP可调节Cortactin(Y421)的磷酸化从而抑制乳腺癌侵袭性伪足，但具体机制尚不清楚。通过蛋白激酶芯片我们筛选出新的分子ALK，我们近期的研究证实ALK与Cortactin结合，且下调DAB2IP的表达可增强二者的结合；此外，降低ALK的表达可显著逆转DAB2IP缺失对侵袭性伪足的促进效应。因此，我们假设ALK介导DAB2IP抑制侵袭性伪足的形成，最终抑制乳腺癌转移。本课题拟完成：1.证实DAB2IP负调控ALK；2.揭示ALK调节Cortactin磷酸化的具体分子机制；3.明确ALK介导DAB2IP调控侵袭性伪足抑制转移；4.基于乳腺癌临床样本库，分析DAB2IP、ALK的表达与肿瘤复发转移的相关性。通过上述研究，力图阐明ALK介导DAB2IP抑制乳腺癌转移的功能及分子机制，为抑制乳腺癌转移提供新的靶点。