"HMGB1-线粒体"作用通路影响胃癌化疗敏感性的分子机制及新型抑制剂TSD作用研究

Chemotherapy is an integral part of the combined treatment of gastric cancer. The anti-cancer sensetivity significantly affect the prognosis. HMGB1 and the integrity of mitochondrial function play key or central roles in the emergence and development of cancer, including gastric cancer. More and more evidences show that they also influence the sensitivity of anti-tumor drugs. The recent studies have identified that HMGB1 was an important regulator of mitochondria, and cross-talk with mitochondria in the related mechanisms. But it is not evident that HMGB1 and mitochondria play their relatively independent roles, or have the common pathway. The further study was necessary to show the effect and mechanism of “HMGB1-mitochondria” regulation pathway on the sensitivity of anti-cancer drugs, especially in gastric cancer. Based on our preliminary work, we present the study to reveal the biological functions and molecular mechanisms of HMGB1 on the maintenance of mitochondria architecture and function integrity, and their effect on the sensitivity of anti-cancer drugs. The main research contents include: 1) The effect of HMGB1 on the sensitivity of chemotherapic drugs to gastric cancer. 2) The effect and mechnism of HMGB1 on the function and architecture of mitochondria. 3) The effect and mechnism of "HMGB1-mitochondria" pathway on the sensitivity of anti-cancer drugs. 4)The effect of a novel HMGB1 inhibitor, TSD, on the biological behaviors of gastic cancer cells, including the sensitity of anti-cancer drugs. The associated study will reveal the biological functions and the mechanism HMGB1 in the maintenance of mitocondria integrity, deepen the mechanism study associated with HMGB1 and mitochondria on the sensitivity of the anti-cancer drugs, and accelerate the study of the novel inhibitor targeting HMGB1.

化疗作为胃癌综合治疗重要组成部分，药物敏感性显著影响预后。HMGB1及线粒体功能均可影响化疗药物敏感性，HMGB1是线粒体功能重要调控因子，但“HMGB1-线粒体”作用通路对化疗敏感性的影响和机制，并不明确；新型HMGB1抑制剂的筛选，明确其对胃癌化疗药物敏感性的影响，十分必要。前期研究证实：胃癌存在HMGB1过表达，与预后相关；干扰HMGB1表达，可影响线粒体功能。本课题以胃癌切入点，研究：①HMGB1表达与定位对胃癌化疗药物敏感性的影响。②HMGB1对线粒体功能的调控作用，及其分子机制。③“HMGB1-线粒体”作用通路在胃癌药物敏感性调控中的地位和精确分子机制。④新型HMGB1抑制剂TSD对胃癌细胞生物学行为，包括化疗药物敏感性的影响。本课题将深入胃癌化疗药物敏感性的HMGB1、线粒体相关机制探索，明确新型HMGB1抑制剂的作用，益于胃癌治疗研究。

HMGB1参与胃癌恶性生物学行为的各个环节，HMGB1可通过调控线粒体的功能发挥作用。目前，“HMGB1-线粒体”作用通路的相关分子机制尚不明确，其对胃癌化疗敏感性的影响需要进一步研究。通过筛选特异性HMGB1抑制剂，干扰“HMGB1-线粒体”作用通路，可能有效提高胃癌化疗敏感性。本课题利用RNA干扰和基因转染技术，构建稳定的慢病毒载体，分别降低和升高胃癌细胞HMGB1表达水平，发现HMGB1高表达可提高胃癌细胞增殖、迁移和克隆形成能力，抑制细胞凋亡，增强其恶性生物学行为，并影响胃癌细胞线粒体功能状态。利用差异基因筛选技术，发现多个与线粒体功能相关基因出现表达变化。利用生物信息学技术，对多个信号途径进行筛选，并对IFN及MAPK等信号通路其作用途径进行分析，对相关分子的表达进行验证。进一步研究表明，SOCS5等多个分子可影响胃癌细胞生物学行为，其基因多态性与胃癌预后和化疗反应性有关。丹参酮IIA衍生物与HMGB1具有特异性结合能力，在成功制备其新型衍生物TSA20和TSA21的基础之上，证实其可抑制胃癌细胞的增殖，并影响线粒体的功能状态，具有提供化疗药物敏感性的潜能。通过本研究进一步证实“HMGB1-线粒体”作用通过多种分子和分子通路参与胃癌细胞生物学行为的调节。HMGB1及多个相关分子的表达水平和基因多态性与胃癌预后和化疗反应性有关。抑制其作用，可有效改变其恶性生物学行为。新型丹参酮IIA衍生物可抑制胃癌细胞增殖，可能提高胃癌化疗敏感性。该研究将促进胃癌中“HMGB1-线粒体”作用通路相关的机制研究，促进相关胃癌耐药逆转策略的研究，为新型治疗药物的研究提供新的思路。鉴于胃癌细胞中“HMGB1-线粒体”作用通路功能和作用机制的复杂性，需在后继的工作中进一步深入研究。