新分子Ankrd22促进结直肠癌细胞重新获得干细胞特性靶蛋白鉴定及其作用机制研究

项目名称： 新分子Ankrd22促进结直肠癌细胞重新获得干细胞特性靶蛋白鉴定及其作用机制研究

项目编号： No.81472723

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 朱永良

作者单位： 浙江大学

项目金额： 74万元

中文摘要： 肿瘤干细胞是结直肠癌浸润转移和复发主要原因之一。最近发现普通肿瘤细胞可通过重编程不断去分化和重新获得干细胞特性而再生成肿瘤干细胞。因此，阻断肿瘤干细胞再生成是靶向清除结直肠癌干细胞的前提，然目前对结直肠癌细胞重新获得干细胞特性分子机制尚需明了。我们先前发现Ankrd22在结直肠癌干细胞表达显著增加；表达Ankrd22后细胞多停留在干细胞阶段；炎性因子和缺氧可促进Ankrd22转录。提示Ankrd22可能是靶向阻断结直肠癌干细胞再生成一个新的潜在治疗靶点。然目前Ankrd22分子作用机制尚不明了。本研究拟在先前研究基础上通过亲和串联质谱/酵母双杂交筛选和鉴定Ankrd22相互作用靶蛋白并阐明其促进结直肠癌细胞重新获得干细胞特性分子机制；明确炎性因子和缺氧等对Ankrd22的转录调控及对结直肠癌细胞重新获得干细胞能力影响。本研究为今后研制阻断肿瘤干细胞再生成新的低毒性分子靶向药物打下扎实基础。

中文关键词： 结直肠肿瘤；肿瘤干细胞；Ankrd22；重编程；分子机制

英文摘要： Colorectal cancer stem cells (CCSC) contribute greatly to the invasion, metastasis and recurrence in colorectal cancer (CRC). Recent studies have found that differentiated tumor cells could dedifferentiate and regain stemness characteristic, and then transform into CCSC through constant reprogramming. Thus, blocking of CCSC regeneration becomes a premise for target-eradicating CCSC. However, the mechanisms how differentiated tumor cells regain stemness characteristic are yet to be further understood. We previously found that the expression of Ankrd22 increased significantly in CCSC. CRC cells with enforced expression of Ankrd22 were inclined to stay in the stem-cell stage. Inflammatory cytokines and hypoxia also promoted transcription of Ankrd22. These results indicated that Ankrd22 may be a new therapeutic target for blocking of CCSC regeneration. But the molecular mechanisms of Ankrd22 remain unclear. Based on previous results, our current study is aimed to screen and identify the critical candidate molecules of Ankrd22 by affinity chromatography tandem mass spectrometry/yeast two-hybrid systems, clarify the molecular mechanisms of Ankrd22 promoting CRC reprogramming, and investigate how inflammatory cytokines and hypoxia affect transcription of Ankrd22 and CRC reprogramming. This study will lay a solid foundation for developing new molecular targeted drugs with low toxicity for blocking regeneration of cancer stem cells.

英文关键词： colorectal cancer;tumor stem cell;Ankrd22;reprogramming;molecular mechanism