Snail通过调控P-gp表达促进结直肠癌化疗耐药的机制研究

The transcription factor Snail is a key regulator of epithelial-mesenchymal transition (EMT). The Snail-induced EMT in cancer cells results in the acquisition of enhanced migration capability and the induction of chemoresistance. However, the underlying mechanism is not clear. Increasing evidences improved that P-glycoprotein (P-gp), encoded by ABCB1 gene, plays critical role in tumor chemoresistance. Our preliminary studies have revealed that Snail-mediated EMT cancer cells can overexpress ABCB1 and P-gp, which provided a new clue for elucidating Snail-induced chemoresistance. Thus, on the basis of our previous established in vitro models of Snail-mediated EMT and chemoresistance, the major objectives of the present proposal are to evaluate the molecular inner links of Snail induced EMT and chemoresistance formation. Furthermore, we will search for new strategies to inhibit Snail, and then assess the validity and feasibility for increasing tumor chemotherapeutic effect and reducing the risks of tumor metastasis.

转录因子Snail是诱发肿瘤上皮-间质转化(EMT)的关键蛋白。由其诱导发生EMT转化的肿瘤细胞具有侵袭转移的特性，并可引发肿瘤化疗耐药，然而潜在的机制并不清楚。P-糖蛋白（P-gp）是由外排基因ABCB1编码的蛋白质，P-gp在肿瘤化疗耐药过程中的关键作用已被大量证实。我们前期研究发现，经Snail诱发EMT的结直肠癌细胞会高表达ABCB1，并促进P-gp表达，这为阐明Snail介导的EMT导致肿瘤化疗耐药提供了新的线索。据此，本课题拟在前期构建的Snail诱导肿瘤细胞EMT以及由此诱发肿瘤耐药模型的基础上，探讨P-gp在Snail促进结直肠癌化疗耐药过程中的作用，通过多个层面解析Snail调控P-gp生成的内在分子机制，并评价相关干预措施对于改善肿瘤化疗疗效，降低肿瘤转移风险的有效性和可行性。

目的和意义：基于对肿瘤细胞发生上皮间质转化（EMT）伴随化疗耐药性产生的最新认识，本课题拟探讨EMT介导肿瘤化疗耐受的机制，并研究解除EMT介导的肿瘤化疗耐受的可行性策略。研究结果：1. 建立了过表达Snail引起肠癌细胞发生EMT转化的模型，并发现发生EMT转化的细胞获得了对化疗药物的耐受性；2. 探讨了过表达Snail引起肠癌细胞化疗耐药的机制，发现Snail可以通过直接结合在ABCB1基因的启动子上而促进其编码蛋白P-gp的表达，从而促进肠癌细胞化疗耐受性；3. 发现肠癌耐药细胞株获得更强的侵袭转移能力并产生EMT的特性，转录因子Snail和耐药蛋白P-gp表达增多，干扰Snail表达后，EMT现象被逆转，P-gp表达减少，耐药细胞的耐药性下降。4. 证实了P-gp在新型化疗药物组蛋白去乙酰化酶抑制剂引起化疗耐药性过程中发挥的关键作用，发现组蛋白去乙酰化酶抑制剂是通过激活STAT3促进P-gp转录同时提高了ABCB1基因稳定性而提高P-gp蛋白表达。本研究为克服结直肠癌化疗耐药提供了新的靶点和策略。