Exosomal MALAT1在肿瘤相关成纤维细胞促进胰腺癌吉西他滨耐药中的作用机制研究

吉西他滨是胰腺癌化疗的一线药物，但临床普遍存在耐药性，疗效难令人满意。肿瘤相关成纤维细胞（CAFs）参与肿瘤恶性表型维持，外泌体是介导CAF调节肿瘤细胞的重要媒介。课题组前期研究发现：FoxM1与胰腺癌吉西他滨耐药相关，CAF源性外泌体可诱导胰腺癌细胞吉西他滨耐药；MALAT1等多种lncRNA在CAF源性外泌体中显著富集；MALAT1可上调FoxM1表达，该效应依赖于ceRNA机制，MALAT1和FoxM1之间可能存在正反馈调控。由此提出科学假说：CAF源性外泌体携载MALAT1进入胰腺癌细胞，通过ceRNA机制上调FoxM1表达并形成正反馈调节环路，诱导肿瘤细胞耐药。本课题拟通过荧光标记示踪外泌体在CAF和胰腺癌细胞间的传递过程；功能学分析确定外泌体源性MALAT1对吉西他滨耐药的诱导作用；信息学分析及验证阐明MALAT1的具体作用机制。该研究将为逆转胰腺癌吉西他滨耐药提供新思路。

Gemcitabine is the first line chemotherapeutic agent for pancreatic cancer. However, it is clinically ineffective due to resistance arising in pancreatic cancer cells. Cancer-associated fibroblasts (CAFs) have been reported involved in maintenance of various malignant phenotypes of cancer cells such as chemotherapeutic resistance. Exosomes are important bioinformational molecular carriers that mediate the modulation of CAF to cancer cells. Our previous study demonstrated that FoxM1 was involved in modulating gemcitabine resistance of pancreatic cancer cells. CAF-derived exosomes can induce gemcitabine resistance. lncRNAs such as metastasis-associated lung adenocarcinoma transcript 1 (MALAT1).are significantly increased in CAF-derived exosomes. Overexpression of MALAT1 can increase FoxM1 expression, which is ceRNA mechanism dependent. Furthermore, a positive feedback loop may exist between MALAT1 and FoxM1. Here we proposed a hypothesis that CAF-derived MALAT1 can be delivered into cancer cells through exosomes, leading to the ceRNA-dependent induction of FoxM1 and activation of a positive feedback loop, resulting in induction of gemcitabine resistance of pancreatic cancer cells. In this project, we will validate the transmission of exosomes between CAF and cancer cell by fluorescence labeling. Functional analysis will be performed to confirm the effect of exosomal MALAT1 in inducing gemcitabine resistance of pancreatic cancer cells. The specific mechanism of MALAT1 will be explored by informatics analysis. This project will provide a novel idea to reverse the drug resistance of gemcitabine in pancreatic cancer.