热疗诱导肿瘤中STAT3的激活及其干预治疗的机制研究

Hyperthermia is thought to be one of the important cancer therapies following surgery, radiation therapy, chemotherapy and biotherapy, which has been widely used in a variety of tumors. It can damage and kill the tumor cell, inhibit angiogenesis, reduce tumor invasion and metastasis. However, the therapeutic effect of hyperthermia alone is still not ideal due to the thermotolerance produced by tumors.So,there is an urgent need to screen some novel targets or methods which could increase the sensitivity of tumors to hyperthermia to get a better anti-tumor effects. Results from the preliminary studies showed that hyperthermia could induce the activation of STAT3 in tumors. After the intervention of STAT3 inhibitor, the sensitivity of tumors to hyperthermia was significantly increased, and showed an ideal therapeutic effects invivo. It is suggested that STAT3 may be a novel molecule involved in the production of thermotolerance, and a potential target which could eliminate the thermotolerance to enhance the sensitivity of tumors to hyperthermia. This project aimed to identify the differential interacting proteins with STAT3, and to clarify the STAT3 signaling pathway induced by hyperthermia and the anti-tumor mechanism of intervention therapy of STAT3 inhibitor. Futhermore, the fesibility of cancer therapy by targetting the key molecules in the hyperthermia- - STAT3 signaling pathway will also be explored.The implementation of this innovative project will not only provide a theoretical instruction for screening the targets to enhance the anti-tumor effects of hyperthermia, but aslo provide some new and effective ideas for hyperthermia application in clinical trail.

热疗是继手术、放疗、化疗、生物治疗后又一种重要的肿瘤治疗方法，它能直接杀伤肿瘤，抑制新生血管，降低肿瘤的侵袭转移，已被广泛用于肿瘤的治疗。由于肿瘤对热疗易产生耐热性，单独应用热疗的治疗效果仍然不够理想，所以迫切需要寻找增加热疗敏感性的靶点或方法以增强热疗的抗肿瘤作用。在前期工作中，我们发现热疗能够诱导肿瘤中癌基因STAT3的激活，在应用STAT3抑制剂干预后，肿瘤对热疗的敏感性显著增加，表现出良好的抗肿瘤作用，提示STAT3可能与热疗的耐热性有关，是消除肿瘤耐热性，增敏热疗抗肿瘤作用的潜在靶点。本项目拟在前期工作的基础上，以筛选STAT3相互作用差异蛋白为核心，构建热疗诱导肿瘤中STAT3激活的信号通路，阐明STAT3抑制剂增加热疗敏感性的机制，并探讨以热疗-STAT3通路中关键节点分子为靶点进行肿瘤治疗的可行性，为筛选热疗的增敏靶点提供理论依据，为发展新的、有效的热疗治疗方案提供新思路。

目前，肿瘤治疗的手段主要包括：手术、放疗、化疗以及生物治疗等，这些治疗手段在肿瘤的治疗中取得了较好的成绩，但常伴有很强的毒副作用，如肿瘤容易复发或产生耐药性等。热疗作为一种物理治疗方法可以用来治疗肿瘤，其本身毒副作用也很小，但单独应用热疗的抗肿瘤效果仍然不够理想，需要与其它方法联合才能达到较好的治疗效果，这可能与肿瘤对热疗产生耐热性有关。在本课题中，我们发现了热疗能够诱导STAT3的激活，通过应用STAT3小分子抑制剂抑制STAT3的磷酸化后，热疗的抗肿瘤作用显著增强。同时，研究发现热疗联合STAT3小分子抑制剂的抗肿瘤作用主要是通过抑制肿瘤细胞增殖，诱导肿瘤细胞凋亡，抑制促新生血管生长因子VEGF的表达及减少肿瘤新生血管的数量等方面抑制肿瘤的生长。深入的研究发现，热疗主要是通过激活AKT的磷酸化并与STAT3发生直接的相互作用诱导STAT3的激活。综上所述，我们从体内、体外两个方面阐释了STAT3抑制剂增强热疗抗肿瘤作用的机制，揭示了热疗诱导STAT3激活的分子机制，它主要是通过AKT的磷酸化来激活STAT3的。该研究提示STAT3的激活可能是肿瘤产生耐热性的另一个原因，为筛选热疗的增敏靶点提供了理论基础，为发展新的、更加有效的热疗联合治疗方案提供了新的思路。