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

Abstract

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.

Natural killer cell–derived extracellular vesicles in cancer therapy

“…NK‐EVs are also shown to deliver regulatory miRNAs to cancer cells, which could be an alternative tumour‐targeting mechanism of NK‐EVs. NK‐EVs have in two independent studies been shown to contain miR‐186 28 or miR‐3607‐3p 30 . Both miR‐3607‐3p and miR186 act as tumour suppressors, and downregulation of either in cancer tissues predicts poor patient prognosis 31,32 .…”

“…Both miR‐3607‐3p and miR186 act as tumour suppressors, and downregulation of either in cancer tissues predicts poor patient prognosis 31,32 . In vitro, NK‐EVs were able to transfer their miR‐3607‐3p cargo to pancreatic cancer cells, but functional effects of this interaction was not investigated 30 . In another study, NK‐EVs delivered miR‐186 to neuroblastoma cell lines (LAN‐5 and CHLA‐136) upon overnight co‐culture and exerted cytotoxicity in a miR‐186‐dependent manner 28 .…”

Extracellular Vesicles Orchestrate Immune and Tumor Interaction Networks

“…In addition, NK cell-derived EVs have been shown to shuttle certain miRNAs that induce an anti-tumor response even in immunosuppressive TMEs [ 98 ], where they can exert cytotoxic effects specifically against tumor cells [ 32 ]. Indeed, the newly studied miR-3607-3p is found to be enriched in the EVs of NK cells as a way to deliver them to pancreatic cancer cells [ 99 ]. NK cell- and EV-derived miR-3607-3p inhibited the proliferation, migration and invasion of pancreatic cancer cells through the inhibition of IL-26 [ 99 ].…”

“…Indeed, the newly studied miR-3607-3p is found to be enriched in the EVs of NK cells as a way to deliver them to pancreatic cancer cells [ 99 ]. NK cell- and EV-derived miR-3607-3p inhibited the proliferation, migration and invasion of pancreatic cancer cells through the inhibition of IL-26 [ 99 ]. These findings are consistent with the suppressive role of miR-3607-3p that has been reported in non-small cell lung cancer (NSCLC), where it has been shown to induce cell cycle arrest and inhibit tumor growth and metastasis [ 100 ].…”

“…These findings are consistent with the suppressive role of miR-3607-3p that has been reported in non-small cell lung cancer (NSCLC), where it has been shown to induce cell cycle arrest and inhibit tumor growth and metastasis [ 100 ]. Interestingly, miR-3607-3p has also been reported to be downregulated in both NSCLC and pancreatic cancer tissues, and its expression can be used as a prognostic predictor for survival [ 99 , 100 ]. In neuroblastoma, NK cell- and EV-derived miR-186 plays a similar role in suppressing cancer cell growth and preventing TGFβ1-dependent immune escape [ 89 ].…”