LXR/mTOR信号通路在胃癌化疗增敏中的作用及其机制研究

Chemotherapy resistance is the main cause of gastric cancer progression and poor prognosis. Thus, study of the chemotherapy resistance mechanism of gastric cancer and discovering therapeutic methods of antagonizing chemoresistance should be put on the agenda. Our preliminary study shows that liver X receptors (LXRs) may antagonize activated autophagy of gastric cancer cells by chemotherapeutic agents via activating mTOR signaling pathway and play a role of chemosensitization. To identify this scientific hypothesis, we intend to study the effect of LXRs activation in the regulation of mTOR signaling pathway, gastric cancer cell autophagy, apoptosis and proliferation as well as chemotherapy response in vitro, in vivo and clinical tissue samples, and clarify that LXRs inhibit chemotherapy drugs such as oxaliplatin induced gastric cancer cell autophagy through the activation of mTOR signaling pathways, playing the role of inducing apoptosis and inhibiting cell proliferation, which may provide scientific basis for the combination of LXRs agonist and oxaliplatin in the treatment of stomach cancer and chemosensitization. To best of our knowledge, no reported studies link LXR signaling pathway to mTOR signaling pathway and it is also the first time to study LXR agonist as a potential chemosensitization agent in treatment of gastric cancer,which has important theoretical significance and potential clinical value.

化疗耐药是造成胃癌进展和预后不良的主要原因，因此深入研究胃癌化疗抵抗机制，寻找逆转胃癌耐药的治疗方法是临床亟需解决的关键问题。我们前期研究提示：肝X受体(LXRs)可能通过激活mTOR信号通路，拮抗化疗药物激活的胃癌细胞自噬，发挥胃癌化疗增敏作用。为证实这一科学问题，本项目拟从体外、体内和临床组织样本三个层面入手，研究LXRs激活对胃癌细胞mTOR信号通路的调控作用及其对胃癌细胞自噬、凋亡和增殖以及化疗疗效的影响，明确LXRs通过激活mTOR信号通路、拮抗奥沙利铂等化疗药物激活的胃癌细胞自噬，发挥诱导细胞凋亡和抑制细胞增殖的作用，为LXRs激动剂和奥沙利铂联合治疗胃癌以及奥沙利铂化疗增敏提供科学依据。本项目首次将LXR信号通路和mTOR信号通路联系起来，也是第一个探索LXRs激动剂作为胃癌潜在化疗增敏药物的研究，具有重要的理论意义和潜在的临床应用价值。

目前，胃癌化疗抵抗是导致胃癌进展和预后不良的关键因素，因此探究胃癌细胞耐药机制，寻找逆转胃癌化疗抵抗的治疗方法是临床亟需解决的关键问题。大量研究证实，LXRs多种肿瘤组织中呈低表达，且过表达LXRs可明显抑制肿瘤增殖。该项目研究结果证实，LXRs通过调控mTOR信号通路，抑制胃癌细胞增殖和自噬，促进其凋亡，进而起到化疗增敏的作用。另外，通过对124例胃癌患者临床样本的临床病理分析，本课题组还发现LXRα的表达与胃癌分化程度呈正相关，于是分别从体内、体外实验入手，证实了LXRα通过调控Wnt/β-catenin信号通路影响胃癌细胞的分化，通过PA28γ/p53途径抑制胃癌细胞增殖和迁移能力。