TTLL6在缺氧/酸中毒微环境下对食管鳞癌耐药逆转的作用及机制研究

Multidrug resistance is one of the fundamental reason for the failure of chemotherapy in esophageal carcinoma，and it occurs more readily in the microenvironment of hypoxia and acidosis.There is no better solution at present. Our previous study found that TTLL6 expression increased significantly when esophageal cancer cisplatin-induced drug resistance reversed in hypoxia and acidosis microenvironment,with esophageal carcinoma cell's cisplatin resistance index falling by 72%.We put forward a hypothesis:the expression of TTLL6 and its signal pathway mediating activation may play an important role in drug resistance reversal of esophageal carcinoma cells in hypoxia and acidosis microenvironment.In this study,we will use the resistant esophageal squamous cell carcinoma cell line as cell model, and construct the TTLL6 gene's overexpression and RNAi vectors for further study. The fluorescence quantitative PCR and other molecular biological techniques will be used to investigate the correlation between level of TTLL6 in esophageal cancer cell and resistance index in hypoxia/acidosis microenvironment in vivo and in vitro. We will also study the role of TTLL6 in esophageal cancer chemotherapy drug resistance reversal and the possible signal transduction mechanism. Therefore we will discuss the roles and mechanism of TTLL6 in esophageal cancer chemotherapy drug resistance reversal.The research is expected to provide new targets for intervention for esophageal cancer chemotherapy drug resistance reversal.

食管癌的多药耐药是化疗失败的根本原因之一，而缺氧/酸中毒微环境下耐药更易发生，目前尚无较好的解决方法。我们前期研究发现：缺氧/酸中毒微环境下当顺铂诱导耐药的食管癌耐药性逆转时，TTLL6表达显著上升。进一步的预实验发现：缺氧/酸中毒微环境下升高耐药食管癌细胞的TTLL6表达后其对顺铂的耐药指数下降72%。据此我们提出假设：食管癌细胞在缺氧/酸中毒微环境下TTLL6的表达及其介导的信号通路活化在化疗耐药逆转中发挥了重要作用。本研究以耐药食管鳞癌细胞为研究对象，构建TTLL6基因过表达及干扰载体，运用Qt-PCR等分子生物学技术，在细胞及动物水平研究缺氧/酸中毒微环境下食管癌细胞TTLL6与耐药指数间的内在联系，以及TTLL6在食管癌化疗耐药逆转中的作用及可能的信号转导机制。通过本研究，将深入探讨TTLL6在食管癌耐药逆转中的作用及调控机制，研究结果有望为食管癌化疗耐药的逆转提供新的干预靶点。