Department of Pancreatic and Thyroidal Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
Department of Pancreatic and Thyroidal Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China.
Life Sci. 2020 Aug 15;255:117857. doi: 10.1016/j.lfs.2020.117857. Epub 2020 May 27.
AIMS: To explore the pro-metastatic role of exosomes derived from highly invasive pancreatic cancer cell and the associated aberrant expression of exosomal microRNAs (miRNAs). MAIN METHODS: Weakly invasive PC-1 cells were treated with exosomes of highly invasive PC-1.0 cells to determine the pro-metastatic effect of PC-1.0 derived exosomes. The exosomal miRNA profile was further investigated using high-throughput sequencing. The level of miR-125b-5p in highly and weakly invasive pancreatic cancer cells was further determined. Pancreatic cancer cells transfected with miR-125b-5p mimic and inhibitor were used to explore the effect of miR-125b-5p on migration, invasion and epithelial-to-mesenchymal transition (EMT). Treatment with PC-1.0 derived exosome and Western blot assay were performed to validate STARD13 as a target of exosomal miR-125b-5p in pancreatic cancer. KEY FINDINGS: PC-1.0 derived exosomes promoted the migration and invasion of weakly invasive PC-1 cells. miRNA sequencing revealed 62 miRNAs upregulated in PC-1.0 derived exosomes. miR-125b-5p most significantly promoted migration and invasion and was associated with metastasis in pancreatic cancer. Further, miR-125b-5p was upregulated in highly invasive pancreatic cancer cells and increased migration, invasion, and EMT. Moreover, its upregulation was associated with activation of MEK2/ERK2 signaling. The tumor suppressor STARD13 was directly targeted by miR-125b-5p in pancreatic cancer, which was associated with good prognosis and was suppressed by exosomes derived from highly invasive cancer cells. SIGNIFICANCE: This study explored the pro-metastatic role of exosomes derived from highly invasive pancreatic cancer cells and the associated aberrant expression of exosomal miRNAs, which may help to elucidate the metastatic mechanism of pancreatic cancer.
目的：探讨来源于高侵袭性胰腺癌细胞的外泌体的促转移作用及其相关外泌体 microRNAs（miRNAs）的异常表达。
主要方法：用高侵袭性 PC-1.0 细胞的外泌体处理弱侵袭性 PC-1 细胞，以确定 PC-1.0 衍生的外泌体的促转移作用。进一步使用高通量测序研究外泌体 miRNA 谱。进一步测定高侵袭性和弱侵袭性胰腺癌细胞中 miR-125b-5p 的水平。用 miR-125b-5p 模拟物和抑制剂转染胰腺癌细胞，以探讨 miR-125b-5p 对迁移、侵袭和上皮-间充质转化（EMT）的影响。用 PC-1.0 衍生的外泌体处理并进行 Western blot 检测，以验证 STARD13 是胰腺癌细胞中外泌体 miR-125b-5p 的靶标。
主要发现：PC-1.0 衍生的外泌体促进了弱侵袭性 PC-1 细胞的迁移和侵袭。miRNA 测序显示，PC-1.0 衍生的外泌体中有 62 个 miRNA 上调。miR-125b-5p 最显著地促进了迁移和侵袭，与胰腺癌细胞的转移有关。此外，miR-125b-5p 在高侵袭性胰腺癌细胞中上调，并增加了迁移、侵袭和 EMT。此外，其上调与 MEK2/ERK2 信号的激活有关。在胰腺癌细胞中，肿瘤抑制因子 STARD13 是 miR-125b-5p 的直接靶标，其与良好的预后相关，并被高侵袭性癌细胞衍生的外泌体抑制。
意义：本研究探讨了来源于高侵袭性胰腺癌细胞的外泌体的促转移作用及其相关外泌体 miRNAs 的异常表达，这可能有助于阐明胰腺癌的转移机制。
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