Wu Rongxiang, Su Zhan, Zhao Le, Pei Ruifeng, Ding Yiren, Li Deqiang, Zhu Shuo, Xu Lu, Zhao Wei, Zhou Wuyuan
Jiangsu University, Zhenjiang 212013, China.
Department of Hepatopancreatobiliary Surgery, Xuzhou Cancer Hospital, Xuzhou 221005, China.
Stem Cells Int. 2023 Jan 30;2023:6510571. doi: 10.1155/2023/6510571. eCollection 2023.
It is becoming increasingly evident that key mechanisms of mesenchymal stem cell (MSC) efficacy appear to associate with paracrine activities, and the delivery of cargos through extracellular vesicles (EVs) controls the mechanistic actions of MSCs. Thus, this study clarified a possible mechanism by which EV-encapsulated NEAT1 from adipose-derived mesenchymal stem cells (ADSCs) might mediate gemcitabine resistance in pancreatic cancer (PCa). Microarray profile suggested a differentially expressed lncRNA NEAT1 in PCa, and we determined its expression in PCa cells. NEAT1 was found to be upregulated in PCa. The binding affinity among NEAT1, miR-491-5p, and Snail was identified through bioinformatic analysis and experimental validation. NEAT1 competitively bound to miR-491-5p to elevate Snail expression and diminish SOCS3 expression. PCa cells were cocultured with EVs extracted from ADSCs, followed by assessment of malignant phenotypes, tumorigenesis, and gemcitabine resistance of PCa cells using gain- or loss-of-function experiments. ADSC-derived EVs carrying NEAT1 promoted PCa cell proliferation, migration, and gemcitabine resistance and enhanced tumorigenicity by inhibiting miR-491-5p and SOCS3 and upregulating Snail. Collectively, the findings from our study found a new potential strategy for gemcitabine resistance in PCa by illustrating the mechanistic insights of oncogenic ADSC-derived EVs-loaded NEAT1 via regulating the miR-491-5p/Snail/SOCS3 axis.
越来越明显的是，间充质干细胞（MSC）发挥功效的关键机制似乎与旁分泌活动有关，通过细胞外囊泡（EV）递送货物可控制MSC的作用机制。因此，本研究阐明了一种可能的机制，即脂肪来源的间充质干细胞（ADSC）分泌的包裹NEAT1的EV可能介导胰腺癌（PCa）对吉西他滨的耐药性。基因芯片分析表明PCa中lncRNA NEAT1表达存在差异，我们测定了其在PCa细胞中的表达。发现NEAT1在PCa中上调。通过生物信息学分析和实验验证确定了NEAT1、miR-491-5p和Snail之间的结合亲和力。NEAT1竞争性结合miR-491-5p以提高Snail表达并降低SOCS3表达。将PCa细胞与从ADSC中提取的EV共培养，然后通过功能获得或缺失实验评估PCa细胞的恶性表型、肿瘤发生和对吉西他滨的耐药性。携带NEAT1的ADSC来源的EV通过抑制miR-491-5p和SOCS3并上调Snail来促进PCa细胞增殖、迁移和对吉西他滨的耐药性，并增强肿瘤发生能力。总的来说，我们的研究结果通过阐明致癌性ADSC来源的负载NEAT1的EV通过调节miR-491-5p/Snail/SOCS3轴的作用机制，为PCa对吉西他滨耐药性找到了一种新的潜在策略。
