MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor.
MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor.
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DOI：
10.18632/oncotarget.7651
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发表时间：
2016-03-29
期刊：
影响因子：
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通讯作者：
Prakash J
中科院分区：
文献类型：
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作者：
Kuninty PR;Bojmar L;Tjomsland V;Larsson M;Storm G;Östman A;Sandström P;Prakash J
胰腺星状细胞（PSC）是胰腺肿瘤间质中癌症相关成纤维细胞（CAF）的关键前体细胞。在这项研究中，我们探索了miRNA作为肿瘤间质中的治疗靶点，并发现miR-199 a-3 p和miR-214- 3 p在患者来源的胰腺CAF和TGF-β激活的人PSC（hPSC）中诱导。使用发夹抑制剂抑制miR-199 a/-214可显著抑制TGFβ诱导的分化标志物（例如α-SMA、胶原、PDGFβR）、迁移和增殖。此外，与对照抗miR相比，用抗miR-199 a/-214转染的hPSC的Panc-1和hPSC的异球体获得更小的尺寸。从TGFβ激活的hPSC获得的条件培养基诱导肿瘤细胞生长和内皮细胞管形成。有趣的是，这些诱导在用抗miR-199 a或miR-214转染的hPSC中被废除。此外，IPA分析揭示了与miR-199 a（TP 53、mTOR、Smad 1）和miR-214（PTEN、Bax、ING 4）相关的信号通路。总之，这项研究揭示了miR-199 a-3 p和miR-214- 3 p是PSC激活和PSC诱导的促肿瘤作用的主要调节因子，代表它们是胰腺癌的关键治疗靶点。
Pancreatic stellate cells (PSCs) are the key precursor cells for cancer-associated fibroblasts (CAFs) in pancreatic tumor stroma. In this study, we explored miRNA as therapeutic targets in tumor stroma and found miR-199a-3p and miR-214-3p induced in patient-derived pancreatic CAFs and TGF-β-activated human PSCs (hPSCs). Inhibition of miR-199a/-214 using hairpin inhibitors significantly inhibited TGFβ-induced differentiation markers (e.g. α-SMA, collagen, PDGFβR), migration and proliferation. Furthermore, heterospheroids of Panc-1 and hPSCs attained smaller size with hPSCs transfected with anti-miR-199a/-214 compared to control anti-miR. The conditioned medium obtained from TGFβ-activated hPSCs induced tumor cell growth and endothelial cell tube formation. Interestingly, these inductions were abrogated in hPSCs transfected with anti-miR-199a or miR-214. Moreover, IPA analyses revealed signaling pathways related to miR-199a (TP53, mTOR, Smad1) and miR-214 (PTEN, Bax, ING4). Taken together, this study reveals miR-199a-3p and miR-214-3p as major regulators of PSC activation and PSC-induced pro-tumoral effects, representing them as key therapeutic targets in pancreatic cancer.