宫颈癌中TGF-β1诱导肿瘤干细胞介导顺铂耐药的分子机制研究

Chemoresistance is a significant clinical challenge in the management of advanced cervical cancer. Studies from our group and others have showed that TGF-β signaling pathway can mediate chemotherapy resistance. However, the underlying mechanisms of how TGF-β pathway is activated and causes chemoresistance are not well understood. In our preliminary studies, we found that TGF-β1 plays an important role in the maintenance and formation of cancer stem cells (CSCs). Furthermore, treatment with cisplatin, a commonly used drug for advanced cervical cancer, can activate TGFβ signaling by increasing the amount of extracellular TGFβ1 in cervical cancer cell lines. Therefore, we hypothesize that cisplatin may stimulate TGFβ1 secretion and/or latent TGFβ1 activation resulting in CSC formation to cause drug resistance in human cervical cancer and the combination therapy with a TGFβ inhibitor and cisplatin should block cisplatin/TGFβ-induced CSC formation leading to synergistic inhibition of cervical cancer growth and metastasis. We propose to investigate the correlation between TGF-β1 and cisplatin resistance, and whether cisplatin stimulates TGFβ1 secretion or latent TGFβ1 activation, resulting in CSC formation and cisplatin resistance in cervical carcinoma with various in vitro approaches. We will further investigate whether combination therapy with BGeRII, a novel pan-TGFβ inhibitor, and cisplatin can produce a synergistic anti-tumor activity in vivo. This study aims to determine the role of TGF-β1 signaling pathway in cisplatin resistance in cervical cancer and to provide new strategies for the treatment of this highly prevalent disease in Chinese women.

化疗耐药已成为目前局部晚期宫颈癌的治疗难点。最近研究表明TGF-β1可能通过调控肿瘤干细胞介导顺铂耐药形成，但机制未明。本课题组前期研究证实宫颈癌中顺铂耐药的形成与TGF-β1相关，TGF-β1是调控肿瘤干细胞产生的重要因素。进一步，我们的预实验发现顺铂可以增加宫颈癌细胞外TGF-β1含量，进而激活TGF-β信号通路。由此推测顺铂通过促进宫颈癌细胞分泌或活化TGF-β1，从而诱导宫颈癌肿瘤干细胞形成，最终引起宫颈癌细胞对顺铂的耐药。为此本项目拟通过体内、外实验，以TGF-β1为切入点，探讨顺铂激活TGF-β信号通路及诱导肿瘤干细胞产生的机制，从而揭示宫颈癌中TGF-β1调控肿瘤干细胞介导顺铂耐药形成的分子机制。同时探索本课题组研发的一种新型的TGF-β抑制剂（BGeRII）阻断TGF-β信号通路后是否增强顺铂抗宫颈癌的作用，为解决宫颈癌的化疗耐药提供新的实验依据和治疗思路。

放化疗耐药是影响妇科恶性肿瘤预后的主要原因，最近研究表明TGF-β1可能通过调控肿瘤干细胞介导顺铂耐药形成，但机制未明。本研究首先采用生物信息学方法发现卵巢癌中TGF-β1及其信号通路是受化疗调控的关键信号通路，并在宫颈癌患者组织中验证了化疗可激活宫颈癌组织中TGFβ信号通路，接着在宫颈癌以及卵巢癌细胞中证实常用化疗药物包括顺铂、紫杉醇、喜树碱和表阿霉素均可激活TGF-β信号通路，随后证实化疗药物通过刺激肿瘤细胞中TGFβ1的产生和分泌，活化TGFβ信号，促进上皮间质转化和肿瘤干性特征，从而降低化疗敏感性。最后通过动物实验进一步验证本团队自主研发的新型TGFβ抑制剂RER通过阻断顺铂活化的TGF-β信号通路,逆转顺铂刺激的上皮间质转化、肿瘤干性特征，从而增强顺铂抗肿瘤作用。本研究在国际上率先解析了TGF-β1调控化疗反应的机制，同时验证本课题组自主研发的一种新型的TGF-β抑制剂（RER）阻断TGF-β信号通路后增强化疗药物抗肿瘤的作用，本研究为解决妇科恶性肿瘤的化疗耐药提供新的实验依据和治疗思路。