Department of General Surgery, Peking University First Hospital, Beijing, 100034, China.
Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Cancer Lett. 2020 Oct 10;490:20-30. doi: 10.1016/j.canlet.2020.06.009. Epub 2020 Jun 23.
Exosomes play important role in tumor microenvironment, and mediate the crosstalk between pancreatic cancer (PC) cells and matrix components including pancreatic stellate cells (PSCs) to regulate pancreatic cancer progression. Here we isolated primary PSCs from PC patients, and demonstrated that PSC-derived exosomes could be internalized by PC cells to promote cell proliferation. Furthermore, we identified that miR-5703 in the exosomes acted as a driver of cell proliferation and its inhibitor suppressed the function of exosomes to promote PC cell proliferation. miR-5703 directly bound to the 3'UTR of CMTM4 and downregulated its expression. CMTM4 knockdown promoted PC cell proliferation, while overexpression of CMTM4 suppressed PC cell proliferation both in vivo and in vitro. Mechanistically, we revealed that CMTM4 suppressed PI3K/Akt pathway via downregulating PAK4. In conclusion, our results suggest that PSC-derived exosomal miR-5703 could target CMTM4 in PC cells and promote cell proliferation due to PAK4 activated PI3K/Akt pathway.
外泌体在肿瘤微环境中发挥重要作用，并介导胰腺癌（PC）细胞与包括胰腺星状细胞（PSC）在内的基质成分之间的串扰，以调节胰腺癌的进展。在这里，我们从 PC 患者中分离出原代 PSCs，并证明 PSC 来源的外泌体可以被 PC 细胞内化，从而促进细胞增殖。此外，我们鉴定出外泌体中的 miR-5703 可作为细胞增殖的驱动子，其抑制剂可抑制外泌体促进 PC 细胞增殖的功能。miR-5703 可直接结合 CMTM4 的 3'UTR 并下调其表达。CMTM4 的敲低促进了 PC 细胞的增殖，而 CMTM4 的过表达无论是在体内还是体外均抑制了 PC 细胞的增殖。从机制上讲，我们揭示了 CMTM4 通过下调 PAK4 来抑制 PI3K/Akt 通路。总之，我们的结果表明，PSC 来源的外泌体 miR-5703 可以通过激活 PI3K/Akt 通路来靶向 PC 细胞中的 CMTM4，从而促进细胞增殖。
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