潜在的Tβ4/ILK/PI3K/Akt信号通路介导肝癌干细胞对索拉非尼的耐受作用及克服方案的探索

项目名称： 潜在的Tβ4/ILK/PI3K/Akt信号通路介导肝癌干细胞对索拉非尼的耐受作用及克服方案的探索

项目编号： No.81201721

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 曹璐

作者单位： 中国人民解放军第二军医大学

项目金额： 23万元

中文摘要： 索拉非尼治疗晚期肝癌有一定疗效但效果有限。我们发现肝癌干细胞对索拉非尼明显耐受，肝癌干细胞中PI3K/Akt通路关键分子表达上调，因而推测耐受机制可能是该通路的代偿性活化。基因组芯片结果不仅佐证此推断，且提示与胸腺肽β4（Tβ4）明显相关。Tβ4与肿瘤密切相关，但目前在肝癌中的研究仍是空白。预实验证明Tβ4、整合素连接激酶（ILK）表达与PI3K/Akt活跃程度呈正相关。故提出假设，潜在的Tβ4/ILK/PI3K/Akt通路介导肝癌细胞尤其是肝癌干细胞对索拉非尼的耐受。本项目将广泛调查Tβ4、ILK和PI3K/Akt信号分子在肝癌细胞、肝癌干细胞中的表达，鉴定肝癌（干）细胞耐受索拉非尼的分子机制；寻找合适的拮抗剂阻断该通路，研究其联合索拉非尼在体外及体内杀伤肝癌（干）细胞的效果。综合细胞增殖、干性特征、瘤体生长、血管生成等指标，提出克服肝癌细胞尤其是肝癌干细胞对索拉非尼耐受的潜在解决方案。

中文关键词： 索拉非尼；肝癌干细胞；循环肿瘤细胞；耐药机制；疗效预测

英文摘要： Sorafenib treatment for advanced liver cancer has certain effect, but not satisfactary currently. We found liver cancer stem cells (LCSCs) were significantly resistant to sorafenib and key molecules of PI3K/Akt pathway were up-regulated in liver cancer stem cells. We speculated that compensatory activation of PI3K/Akt pathway may be the principle mechanism of sorafenib resistance. We performed Human Genome Array GeneChip? in LCSCs and the parental cells, and the results not only verified the up-regulated PI3K/Akt pathway, but also indicated thymosin β4 (Tβ4) as a significant sorafenib resistance gene. Tβ4 play a role in tumorigenesis and metastasis, however, there are no literature reports in liver cancer. Our experimental results proved Tβ4, integrin linked kinase (ILK) and PI3K/Akt pathway were positively correlated. So we assume the potential Tβ4/ILK/PI3K/Akt pathway may mediate sorafenib resistance in liver cancer, especially in LCSCs. In this project, we will widely explore Tβ4, ILK and PI3K/Akt signal molecules in liver cancer cell lines and LCSCs, identifying the molecular mechanism of sorafenib resistance. Then, we will find an appropriate antagonist to block this pathway and investigate the anti-tumor effect combined with sorafenib, both in vitro and in vivo. We intent to propose a potential solution to

英文关键词： Sorafenib；Liver cancer stem cells；Circulating tumor cells；Resistance mechanisms；Efficacy prediction