PMID- 34543801 OWN - NLM STAT- MEDLINE DCOM- 20220302 LR - 20220302 IS - 1532-3072 (Electronic) IS - 0040-8166 (Linking) VI - 73 DP - 2021 Dec TI - Exosomes secreted from human umbilical cord mesenchymal stem cells promote pancreatic ductal adenocarcinoma growth by transferring miR-100-5p. PG - 101623 LID - S0040-8166(21)00139-7 [pii] LID - 10.1016/j.tice.2021.101623 [doi] AB - PURPOSE: Although human umbilical cord mesenchymal stem cells (hucMSCs) can contribute to the growth of tumors, including pancreatic ductal adenocarcinoma (PDAC), however, little is known about the exact mechanisms by which the exosomes secreted from hucMSCs (hucMSCs-exo) have an oncogenic effect on the physiopathology of PDAC. The effects of hucMSCs on tumor development are attributed to hucMSCs-exo, which deliver unique proteins and miRNAs to cancer cells. METHODS: HucMSCs and exosomes were isolated and confirmed via transmission electron microscopy, nanoparticle tracking analysis and western blot. The nude mice were inoculated subcutaneously on both flanks with human pancreatic cancer Panc-1 cells (1 x 10(6)), and hucMSCs-exo were directly administered via intratumoral injection once a day for three days each week. Cell proliferation assays were performed using a Cell Counting Kit-8 assay and the cell invasion assay was performed using Transwell assay. The miRNA data were predicted and analyzed by miRanda software. The analysis of the target genes of the miRNAs was proformed with the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. RESULTS: Firstly, we observed that hucMSCs-exo promoted Panc-1 and BxPC3 cell growth by increasing proliferation and migration in vitro. Secondly, in a xenograft tumor model, hucMSCs-exo increased the growth of Panc-1 cells. Thirdly, high-throughput sequencing of hucMSCs-exo showed that hsa-miR-148a-3p, hsa-miR-100-5p, hsa-miR-143-3p, hsa-miR-21-5p and hsa-miR-92a-3p were highly expressed. For the five identified miRNAs, 1308 target genes were predicted by miRanda software. From the GO and KEGG analyses of the target genes of the identified miRNAs, it was found that the main GO function was the regulation of cellular glucuronidation, and the main KEGG metabolic pathway involved the metabolism of ascorbic acid and aldehyde acid. These processes are related to the occurrence and development of pancreatic cancer. Finally, we observed that miR-100-5p promoted Panc-1 and BxPC3 cell growth in vitro and in vivo. CONCLUSION: Here, by utilizing exosomes secreted from hucMSCs, we systematically investigated the effects of hucMSCs-exo on PDAC growth in vitro and in vivo for the first time. Building on these results, we provided new insights into the role of hucMSCs-exo in the PDAC growth and revealed the attractive communication between hucMSCs and PDAC cells that occurs through MSCs-exosomes-miRNAs. CI - Copyright (c) 2021. Published by Elsevier Ltd. FAU - Ding, Yixuan AU - Ding Y AD - Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China; Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, 100053, China. FAU - Mei, Wentong AU - Mei W AD - Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China; Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, 100053, China. FAU - Zheng, Zhi AU - Zheng Z AD - Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China; Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, 100053, China. FAU - Cao, Feng AU - Cao F AD - Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China; Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, 100053, China. FAU - Liang, Kuo AU - Liang K AD - Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China. FAU - Jia, Yuchen AU - Jia Y AD - Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China; Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, 100053, China. FAU - Wang, Yuting AU - Wang Y AD - Capital Medical University, Beijing, 100069, China. FAU - Liu, Dachuan AU - Liu D AD - Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China; Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, 100053, China. Electronic address: dachuan_liu@aliyun.com. FAU - Li, Jia AU - Li J AD - Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China; Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, 100053, China. Electronic address: lij@xwhosp.org. FAU - Li, Fei AU - Li F AD - Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China; Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, 100053, China. Electronic address: feili36@ccmu.com.cn. LA - eng PT - Journal Article DEP - 20210814 PL - Scotland TA - Tissue Cell JT - Tissue & cell JID - 0214745 RN - 0 (MIRN100 microRNA, human) RN - 0 (MicroRNAs) SB - IM MH - Adenocarcinoma/genetics/*pathology MH - Carcinoma, Pancreatic Ductal/genetics/*pathology MH - Cell Line, Tumor MH - Cell Proliferation/genetics MH - Exosomes/*metabolism/ultrastructure MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Mesenchymal Stem Cells/*metabolism MH - MicroRNAs/genetics/*metabolism MH - Pancreatic Neoplasms/genetics/*pathology MH - Umbilical Cord/*cytology OTO - NOTNLM OT - Exosomes OT - HucMSCs OT - MiRNAs OT - PDAC OT - Signaling pathways EDAT- 2021/09/21 06:00 MHDA- 2022/03/03 06:00 CRDT- 2021/09/20 20:17 PHST- 2021/04/16 00:00 [received] PHST- 2021/08/10 00:00 [revised] PHST- 2021/08/12 00:00 [accepted] PHST- 2021/09/21 06:00 [pubmed] PHST- 2022/03/03 06:00 [medline] PHST- 2021/09/20 20:17 [entrez] AID - S0040-8166(21)00139-7 [pii] AID - 10.1016/j.tice.2021.101623 [doi] PST - ppublish SO - Tissue Cell. 2021 Dec;73:101623. doi: 10.1016/j.tice.2021.101623. Epub 2021 Aug 14.