DAB2IP通过ZEB1调控结直肠癌转移的功能与机制研究

Recent studies have demonstrated that EMT and CSC play an important role in tumor metastasis. Our previous research showed that DAB2IP, a novel member of the Ras GTPase-activating protein family, functions as a tumor suppressor to inhibit EMT and metastasis in prostate cancer. Recently, our data implies that DAB2IP also plays a role in regulating EMT and CSC of colorectal cancer,however,the underlying mechanism remains unknown. Our preliminary data indicated that DAB2IP can down-regulate ZEB1 mRNA level. ZEB1 is as a transcript factor which plays an important role in EMT and CSC. Thus, we hypothesize that DAB2IP inhibits colorectal cancer metastasis through ZEB1. Our project aims to: 1, Uncover the molecular mechanism of DAB2IP regualting EMT and CSC through ZEB1 in CRC. 2, Confirm the role of DAB2IP regulating EMT and CSC through ZEB1 in animal model. 3, Analyze the clinic relationship between DAB2IP, ZEB1 expression and distal metastasis as well as Duke's stage in colorectal cancer patients. Overall, our proposal will provides strong evidence to the conclusion that loss of DAB2IP contributes to colorectal cancer progression by activating EMT and enhancing the self-renewal of CSCs, which might benefit for molecualr therapy of colorectal cancer.

上皮细胞间质转化(EMT)及肿瘤干细胞(CSC)在肿瘤转移中起重要作用。我们的前期研究揭示了一个抑制前列腺癌EMT的重要蛋白－DAB2IP；最近又发现DAB2IP还可能调控结直肠癌EMT及CSC,但其下游调控的具体分子机制尚不清楚。我们的预实验提示DAB2IP可下调转录因子ZEB1的表达水平。现已有研究证实ZEB1能同时参与调控EMT与CSC。因此，我们推测DAB2IP通过ZEB1调控EMT及CSC特性，抑制结直肠癌转移。本课题将以结直癌细胞为研究对象，高表达或沉默ZEB1后，检测DAB2IP对EMT及CSC表型的影响；利用小鼠结直肠癌原位种植模型，探讨ZEB1在DAB2IP抑制结直肠癌转移中所起的重要作用；分析DAB2IP和ZEB1表达异常与结直肠癌患者转移及预后的相关性。本研究将初步阐明DAB2IP抑制结直肠癌转移的分子机制，为阻遏肿瘤转移提供潜在治疗靶点。

上皮细胞间质转化（EMT）及肿瘤干细胞（CSC）在肿瘤转移中起重要作用。我们前期研究中揭示了一个抑制前列腺癌EMT的重要蛋白-DAB2IP；最近又发现DAB2IP还可能调控结直肠癌EMT及CSC，但其具体调控机制尚不清楚。本项目主要以结直肠癌细胞为研究对象，检测DAB2IP对EMT及CSC表型的影响，证实DAB2IP调控EMT及CSC是通过NF-κB 信号通路介导的；利用小鼠结直肠癌原位种植模型，探讨DAB2IP在抑制结直肠癌转移中的作用；分析DAB2IP的表达与临床结直肠癌患者转移及预后的相关性。现已完成了该项目的所有研究内容。.该项目的重要研究结果如下：1.我们在体外证实了DAB2IP可以抑制结直肠癌细胞EMT和CSC；2.在体内实验中证实DABIP的缺失可以促进结直肠癌肿瘤细胞的干性获得；3.证实DAB2IP调控结直肠癌EMT及CSC是通过NF-κB 信号通路介导；4.体内实验证实DAB2IP缺失可以促进结直肠癌细胞肝转移；5.在临床结直肠癌患者标本中发现DAB2IP的表达量与患者转移及预后呈负相关性。.通过本项目的完成进一步揭示了抑癌基因DAB2IP的生物学功能，完善了其在调控肿瘤EMT及CSC中的分子机制，为遏制结直肠癌侵袭转移提供新的靶点。