Exosomal lncRNA UCA1 Derived From Pancreatic Stellate Cells Promotes Gemcitabine Resistance in Pancreatic Cancer via the SOCS3/EZH2 Axis.
Exosomal lncRNA UCA1 Derived From Pancreatic Stellate Cells Promotes Gemcitabine Resistance in Pancreatic Cancer via the SOCS3/EZH2 Axis.
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DOI：
10.3389/fonc.2021.671082
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发表时间：
2021
影响因子：
4.7
通讯作者：
Liu Z
中科院分区：
文献类型：
--
作者：
Chi Y;Xin H;Liu Z
胰腺癌预后差，生存率低。本研究旨在探讨胰腺星状细胞（PSCs）分泌的lncRNA uca1负载外泌体在缺氧条件下胰腺癌对吉西他滨（Gem）耐药中的作用，其中包括SOCS3的甲基化和EZH2的募集。从PSCs和缺氧PSCs （HPSCs）中分离外泌体，并与用操纵lncRNA UCA1， EZH2和SOCS3转导的胰腺癌细胞共培养。lncRNA UCA1、EZH2和SOCS3之间的相互作用通过RIP和ChIP分析进行了表征。MTT法、流式细胞术、TUNEL染色、Transwell法检测细胞活力、凋亡、侵袭和迁移。建立Gem耐药胰腺癌细胞系（GemMIA-R3），应用于小鼠胰腺癌异种移植模型，采用MTT法测定Gem敏感性。胰腺癌组织中LncRNA UCA1高表达，SOCS3低表达。缺氧诱导PSCs活化并促进外泌体的释放。低氧psc衍生外泌体（HPSC-EXO）传递的LncRNA UCA1通过募集EZH2调控SOCS3基因区域的组蛋白甲基化水平。体外和体内实验结果证实，负载lncRNA uca1的HPSC-EXO促进小鼠胰腺癌细胞的恶性表型，抑制细胞凋亡，促进Gem耐药和肿瘤发生。在缺氧条件下，由缺氧诱导的PSCs分泌的外泌体将lncRNA UCA1传递到胰腺癌细胞中，lncRNA UCA1招募EZH2并调节SOCS3基因区域组蛋白甲基化水平，从而增强胰腺癌对Gem的耐药性。
Pancreatic cancer is associated with poor prognosis and dismal survival rates. This study aims to investigate roles of lncRNA UCA1-loaded exosomes secreted by pancreatic stellate cells (PSCs) in Gemcitabine (Gem) resistance of pancreatic cancer under hypoxia, which involves the methylation of SOCS3 and EZH2 recruitment. The exosomes were isolated from PSCs and hypoxic PSCs (HPSCs), and co-cultured with pancreatic cancer cells transduced with manipulated lncRNA UCA1, EZH2, and SOCS3. The interaction among lncRNA UCA1, EZH2, and SOCS3 was characterized by RIP and ChIP assays. Next, MTT assay, flow cytometry and TUNEL staining and Transwell assay were used to detect cell viability, apoptosis, invasion, and migration. Gem-resistant pancreatic cancer cell line (GemMIA-R3) was established, which was applied in a mouse xenograft model of pancreatic cancer, with MTT assay to determine Gem sensitivity. LncRNA UCA1 was highly expressed, while SOCS3 was poorly expressed in pancreatic cancer tissues. Hypoxia induced activation of PSCs and promoted release of exosomes. LncRNA UCA1 delivered by hypoxic PSC-derived exosomes (HPSC-EXO) regulated histone methylation level in SOCS3 gene region through recruitment of EZH2. In vitro and in vivo experimental results confirmed that lncRNA UCA1-loaded HPSC-EXO promoted malignant phenotypes, inhibited apoptosis, and promoted Gem resistance of pancreatic cancer cells as well as tumorigenesis in mice. Under hypoxic conditions, exosomes secreted by hypoxia-induced PSCs deliver lncRNA UCA1 into pancreatic cancer cells, where lncRNA UCA1 recruits EZH2 and regulates histone methylation level in SOCS3 gene region, thereby augmenting pancreatic cancer resistance to Gem.
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影响因子：
37.3
作者：
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影响因子：
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发表时间：
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期刊：
Aging
影响因子：
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影响因子：
3
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DOI：
10.1016/j.omtn.2018.09.026
发表时间：
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期刊：
Molecular therapy. Nucleic acids
影响因子：
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通讯作者：
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