CCL2介导胃癌细胞多药耐药及其机制研究

项目名称： CCL2介导胃癌细胞多药耐药及其机制研究

项目编号： No.81502609

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 许文侠

作者单位： 浙江大学

项目金额： 18万元

中文摘要： 化疗耐药是导致胃癌治疗失败的主要原因。尽管肿瘤耐药相关研究较多，但目前临床上仍缺乏逆转耐药的有效手段，而肿瘤细胞分泌性因子在化疗耐药中的作用也知之甚少。在本项目前期研究中，我们诱导建立了顺铂耐药胃癌细胞模型，发现顺铂耐药胃癌细胞呈现多药耐药特征；进一步通过细胞因子筛选、敏感和耐药细胞共培养等方法发现细胞因子CCL2可以促进胃癌细胞耐药性形成，且涉及细胞自噬和凋亡等生物学过程；同时，耐药细胞中PI3K/AKT、STAT-3等CCL2下游信号通路异常激活。因此，我们认为胃癌细胞可能通过自分泌和旁分泌CCL2来影响PI3K/AKT、STAT-3等信号通路，进而抑制细胞自噬和凋亡水平，最终获得多药耐药能力。为验证该假说，本项目将通过分子、细胞、动物、临床等不同水平层次研究，分析CCL2在胃癌细胞多药耐药中的调控及其作用机制，以揭示肿瘤化疗耐药机制，从而为逆转肿瘤耐药和提高化疗疗效提供新的思路。

中文关键词： C07_胃肿瘤；多药耐药；CCL2；凋亡；自噬

英文摘要： Intrinsic or acquired drug resistance is the major cause resulting into the treatment failure of human cancers including gastric cancer. Despite of intensive investigations into drug resistance, there is no clinical approaches effective to reverse drug resistance. In addition, little was known about the contribution of tumor cell-secreted cytokines to drug resistance. In the preliminary study of this project, we have established two gastric cancer cell lines resistant to cisplatin as well as other chemotherapeutic drugs such as ADM and As2O3. Moreover, the secretion of chemokine (C-C motif) ligand 2 (CCL2) was up-regulated and its downstream signaling pathways include PI3K/AKT, STAT-3 were activated in drug resistant cells. CCL2 depletion reversed drug resistance accompanied with the activation of apoptosis and autophagy while exogenous CCL2 conferred drug resistance to gastric cancer cells. Based on these preliminary results, we speculated that gastric cancer cell can secrete CCL2 in an autocrine or paracrine manner to activate PI3K/Akt, STAT-3 signaling, eventually conferring drug resistance. In this study, we will try to prove this hypothesis by exploring the regulation and function of CCL2 in gastric cancer cells resistant or sensitive to cisplatin or other chemotherapeutic drugs. By doing so, we believe that this study will clarify the contribution of CCL2 to drug resistance and be helpful to develop clinical managements to effectively reverse drug resistance and improve chemotherapy efficacy.

英文关键词： gastric cancer;multidrug resistance;CCL2;apoptosis;autophagy