Intraperitoneal transfer of microRNA‐29b‐containing small extracellular vesicles can suppress peritoneal metastases of gastric cancer

Author:

Kimura Yuki1,Ohzawa Hideyuki2,Miyato Hideyo1,Kaneko Yuki1,Kuchimaru Takahiro3,Takahashi Rei1,Yamaguchi Hironori2,Kurashina Kentaro1,Saito Shin1,Hosoya Yoshinori1,Lefor Alan Kawarai1,Sata Naohiro1,Kitayama Joji14ORCID

Affiliation:

1. Department of Surgery Jichi Medical University Hospital Shimotsuke Japan

2. Department of Clinical Oncology Jichi Medical University Hospital Shimotsuke Japan

3. Center for Molecular Medicine Jichi Medical University Shimotsuke Japan

4. Center for Clinical Research Jichi Medical University Hospital Shimotsuke Japan

Abstract

AbstractSmall extracellular vesicles (sEV) contain various microRNAs (miRNAs) and play crucial roles in the tumor metastatic process. Although miR‐29b levels in peritoneal exosomes were markedly reduced in patients with peritoneal metastases (PM), their role has not been fully clarified. In this study, we asked whether the replacement of miR‐29b can affect the development of PM in a murine model. UE6E7T‐12, human bone marrow‐derived mesenchymal stem cells (BMSCs), were transfected with miR‐29b‐integrating recombinant lentiviral vector and sEV were isolated from culture supernatants using ultracentrifugation. The sEV contained markedly increased amounts of miR‐29b compared with negative controls. Treatment with transforming growth factor‐β1 decreased the expression of E‐cadherin and calretinin with increased expression of vimentin and fibronectin on human omental tissue‐derived mesothelial cells (HPMCs). However, the effects were totally abrogated by adding miR‐29b‐rich sEV. The sEV inhibited proliferation and migration of HPMCs by 15% (p < 0.005, n = 6) and 70% (p < 0.005, n = 6), respectively, and inhibited adhesion of NUGC‐4 and MKN45 to HPMCs by 90% (p < 0.0001, n = 5) and 77% (p < 0.0001, n = 5), respectively. MicroRNA‐29b‐rich murine sEV were similarly obtained using mouse BMSCs and examined for in vivo effects with a syngeneic murine model using YTN16P, a highly metastatic clone of gastric cancer cell. Intraperitoneal (IP) transfer of the sEV every 3 days markedly reduced the number of PM from YTN16P in the mesentery (p < 0.05, n = 6) and the omentum (p < 0.05, n = 6). Bone marrow mesenchymal stem cell‐derived sEV are a useful carrier for IP administration of miR‐29b, which can suppress the development of PM of gastric cancer.

Funder

Japan Society for the Promotion of Science

Publisher

Wiley

Subject

Cancer Research,Oncology,General Medicine

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