Data_Sheet_1_RETRACTED: Natural Killer Cell-Derived Exosomal miR-3607-3p Inhibits Pancreatic Cancer Progression by Targeting IL-26.DOCX

Increasing evidences have suggested that natural killer (NK) cells in the tumor microenvironment are involved in the regulation of cancer development. However, the potential biological roles and regulatory mechanisms of NK cells in pancreatic cancer (PC) remain unclear. Co-culture system of NK cells with PC cells is used to test the ability of cancer cell proliferation, migration and invasion both in vitro and in vivo. And tail vein intravenous transfer was used to test metastasis in vivo. Meanwhile, extracellular vesicles (EVs) were separated and examined. Furthermore, reporter assay and Biotin-RNA pull down assay were performed to verify the interaction between molecules. NK cells can inhibit the malignant transformation of co-cultured PC cells both in vivo and in vitro, which requires miR-3607-3p. miR-3607-3p is found enriched in the EVs of NK cells and transmitted to PC cells, and low level of miR-3607-3p predicts poor prognosis in PC patients. It can also inhibit proliferation, migration and invasion of PC cells in vitro. Importantly, IL-26 is found to be a direct target of miR-3607-3p in PC cells. miR-3607-3p enriched in EVs derived from NK cells can inhibit the malignant transformation of PC probably through directly targeting of IL-26.

越来越多的证据表明，肿瘤微环境（tumor microenvironment）中的自然杀伤细胞（natural killer，NK）参与癌症发展的调控过程。然而，胰腺癌（pancreatic cancer，PC）中NK细胞的潜在生物学功能及调控机制仍未明确。本研究采用NK细胞与胰腺癌细胞的共培养体系，分别在体外（in vitro）与体内（in vivo）检测癌细胞的增殖、迁移与侵袭能力；同时通过尾静脉输注实验，在体内检测肿瘤转移情况。此外，研究者分离并检测了细胞外囊泡（extracellular vesicles，EVs）。进一步通过报告基因实验（reporter assay）与生物素-RNA下拉实验（Biotin-RNA pull down assay），验证分子间的相互作用。NK细胞可在体内外抑制共培养胰腺癌细胞的恶性转化，且该过程依赖于miR-3607-3p。研究发现，miR-3607-3p在NK细胞来源的细胞外囊泡中富集，并可被传递至胰腺癌细胞；胰腺癌患者体内miR-3607-3p低表达预示不良预后。该microRNA还可在体外抑制胰腺癌细胞的增殖、迁移与侵袭。尤为重要的是，白细胞介素26（IL-26）被证实为胰腺癌细胞中miR-3607-3p的直接靶基因。综上，NK细胞来源细胞外囊泡所富集的miR-3607-3p，或可通过直接靶向IL-26，进而抑制胰腺癌细胞的恶性转化。