Oxaliplatin-induced upregulation of exosomal miR-424-3p derived from human bone marrow mesenchymal stem cells attenuates progression of gastric cancer cells.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

MicroRNAs*/genetics ; MicroRNAs*/metabolism ; Oxaliplatin*/pharmacology ; Mesenchymal Stem Cells*/metabolism ; Exosomes*/metabolism ; Exosomes*/genetics ; Stomach Neoplasms*/pathology ; Stomach Neoplasms*/genetics ; Stomach Neoplasms*/metabolism ; Stomach Neoplasms*/drug therapy ; Epithelial-Mesenchymal Transition*/drug effects ; Epithelial-Mesenchymal Transition*/genetics; Humans ; Animals ; Mice ; Cell Line, Tumor ; Up-Regulation ; Gene Expression Regulation, Neoplastic/drug effects ; Xenograft Model Antitumor Assays ; Antineoplastic Agents/pharmacology ; Tumor Microenvironment ; Mice, Nude ; Disease Progression

Chemotherapy, particularly with oxaliplatin, is a key treatment for advanced gastric cancer (GC), and exosomes derived from human bone marrow mesenchymal stem cells (hBM-MSCs) play a vital role in the tumor microenvironment. The study aims to elucidate the previously unexplored role of exosomes derived from hBM-MSCs in GC tumorigenesis, especially under the influence of chemotherapy. We conducted an experimental study, utilizing miRNA sequencing and biological experiments, to analyze the tumorigenicity of exosomal miR-424-3p secreted by hBM-MSCs and its target gene RHOXF2 in GC cell lines. The results were confirmed through experimentation using a xenograft mouse model. This study demonstrated the role of hBM-MSCs in the GC microenvironment, focusing on their epithelial-mesenchymal transition (EMT) facilitation through exosomes, which led to enhanced tumorigenicity in GC cells. Intriguingly, this pro-tumor effect was abrogated when hBM-MSCs were treated with oxaliplatin. Exosomal miRNA sequencing revealed that oxaliplatin can upregulate the levels of miR-424-3p in exosomes secreted by hBM-MSCs, thereby inhibiting the EMT process in GC cells. Furthermore, miR-424-3p was identified to target and downregulate RHOXF2 expression, impeding the malignant behavior of GC cells both in vitro and in the mouse model. These findings uncover a potential hidden mechanism of oxaliplatin's anti-tumor action and propose the delivery of miR-424-3p via exosomes as a promising avenue for anti-tumor therapy.
(© 2024. The Author(s).)

Mol Cancer. 2022 Sep 13;21(1):179. (PMID: 36100944)
Mol Cancer. 2020 Mar 19;19(1):62. (PMID: 32192494)
Int J Oncol. 2012 Jan;40(1):93-8. (PMID: 21874235)
Stem Cell Res Ther. 2019 Dec 16;10(1):381. (PMID: 31842978)
BMC Genomics. 2013 May 10;14:319. (PMID: 23663360)
World J Surg Oncol. 2016 Dec 8;14(1):305. (PMID: 27931221)
Nat Rev Mol Cell Biol. 2014 Mar;15(3):178-96. (PMID: 24556840)
Int J Mol Sci. 2023 Feb 09;24(4):. (PMID: 36834913)
Cell Cycle. 2015 Aug 3;14(15):2473-83. (PMID: 26091251)
Oncogene. 2013 Feb 21;32(8):976-87. (PMID: 22469983)
Int J Mol Med. 2021 Dec;48(6):. (PMID: 34676871)
Cancer Sci. 2023 Jul;114(7):2939-2950. (PMID: 36939028)
Front Oncol. 2020 Dec 23;10:567021. (PMID: 33425722)
CA Cancer J Clin. 2021 May;71(3):209-249. (PMID: 33538338)
Cancer Metastasis Rev. 2013 Dec;32(3-4):623-42. (PMID: 23709120)
Cancer Med. 2019 Dec;8(18):7728-7740. (PMID: 31642612)
Int J Mol Med. 2022 Feb;49(2):. (PMID: 34935051)
J Cell Biochem. 2015 Apr;116(4):618-27. (PMID: 25399738)
Cancer Treat Rev. 2018 Apr;65:22-32. (PMID: 29502037)
J Clin Invest. 2013 Jan;123(1):189-205. (PMID: 23318994)
Onco Targets Ther. 2020 Nov 26;13:12201-12211. (PMID: 33273826)
Biomolecules. 2022 Feb 19;12(2):. (PMID: 35204832)
Cancer Sci. 2020 Apr;111(4):1254-1265. (PMID: 32012403)
Onco Targets Ther. 2020 Jun 25;13:6063-6071. (PMID: 32636639)
Int J Oncol. 2019 Jan;54(1):326-338. (PMID: 30365045)
J Cell Mol Med. 2018 Apr;22(4):2478-2487. (PMID: 29392841)
J Exp Clin Cancer Res. 2015 May 20;34:52. (PMID: 25986392)
Stem Cells Int. 2020 Dec 13;2020:8890201. (PMID: 33414831)
Cancer Lett. 2022 Feb 1;526:29-40. (PMID: 34800567)
Pathogens. 2022 Feb 09;11(2):. (PMID: 35215172)
Mol Carcinog. 2017 Mar;56(3):821-832. (PMID: 27500472)
Nat Commun. 2011;2:282. (PMID: 21505438)
Cancer Sci. 2023 Jun;114(6):2499-2514. (PMID: 36942841)

U2004132, N.L. the Joint Funds of the National Natural Science Foundation of China; YXKC2021008, N.L. Leading Talents in Health Science and Technology Innovation for Young and Middle-aged People in Henan Province; 82003041, C.W. the National Natural Science Fund Youth Fund of China; 222102310324, C.W. Key Scientific and Technological Projects in Henan Province

Keywords: RHOXF2; Exosomes; Gastric cancer; Mesenchymal stem cells; Tumor microenvironment; miR-424-3p

0 (MicroRNAs)
04ZR38536J (Oxaliplatin)
0 (MIRN424 microrna, human)
0 (Antineoplastic Agents)

Date Created: 20240801 Date Completed: 20240801 Latest Revision: 20240808

20240808

PMC11294363

10.1038/s41598-024-68922-6

39090292