肿瘤干细胞被认为是肿瘤化疗耐药的重要因素，但目前胃癌肿瘤干细胞对胃癌常用化疗药物5-氟尿嘧啶（5-Fu）的敏感性及其调控机制尚不清楚。团队前期已捕获人原代胃癌肿瘤干细胞，并发现CD44是其特征性标志物（Cell Res. 2012）；与5-Fu共培养后，胃癌肿瘤干细胞中CD44阳性细胞率上升；干扰CD44表达后，胃癌肿瘤干细胞对5-Fu的敏感性提高，且转录因子TAF1、与5-Fu代谢密切相关的DPYD表达下调。据此，我们提出CD44是否可能通过影响TAF1的活性，调控DPYD表达，介导胃癌肿瘤干细胞对5-Fu的敏感性？本课题拟通过CRISPR/CAS9、免疫共沉淀、免疫荧光、定量PCR、Western Blot、动物模型等实验技术，阐明CD44-TAF1-DPYD通路调控胃癌肿瘤干细胞对5-Fu敏感性的分子机制，论证其在胃癌组织中的临床意义，为筛选胃癌对5-Fu治疗耐药的靶点提供实验依据。

Cancer stem cells are thought as the important factor in chemotherapy resistance of tumors. However, it is still not clear that how the sensitivity is and what is the regulating mechanism of gastric cancer stem cells to 5-fluorouracil (5-Fu) as the common drug of chemotherapy of gastric cancer. In the previous researches, our team has captured the primary gastric cancer stem cells from gastric cancer patients and found that CD44 was the specific marker of gastric cancer stem cells (Cell Res. 2012). After co-cultured with 5-Fu, the ratio of CD44 positive cells of gastric cancer stem cells was increased. When knockdown of CD44 expression, the sensitivity to 5-Fu of gastric cancer stem cells was increased, and the expressions of transcriptor TAF1 and the gene DPYD which is closely associated with the metabolism of 5-Fu were down regulated. Based on these results, we propose that whether CD44 could mediate the sensitivity to 5-Fu of gastric cancer stem cells through influencing the activity of TAF1 and regulating the expression of DPYD? This research aims to illustrate the mechanism of CD44-TAF1-DPYD pathway in regulating the sensitivity to 5-Fu of gastric cancer stem cells and the clinical significance of this pathway in gastric cancer tissues through the experiments like CRISPR/CAS9, co-immunoprecipitation, immunofluorescence, quantitative PCR, Western Blot, animal model, et al. This research might provide the experiment evidence in screening the therapeutic targets against 5-Fu resistance of gastric cancer.