Small Extracellular Vesicles from adipose-derived stem cells suppress cell proliferation by delivering the let-7 family of microRNAs in ovarian cancer

Hironori Suzuki; Akira Yokoi; Kaname Uno; Kosuke Yoshida; Masami Kitagawa; Eri Asano-Inami; Seiko Matsuo; Yukari Nagao; Kazuhiro Suzuki; Kae Nakamura; Masato Yoshihara; Satoshi Tamauchi; Yusuke Shimizu; Yoshiki Ikeda; Nobuhisa Yoshikawa; Hiroaki Kajiyama; Yusuke Yamamoto

doi:10.1016/j.bbrc.2023.09.022

Small Extracellular Vesicles from adipose-derived stem cells suppress cell proliferation by delivering the let-7 family of microRNAs in ovarian cancer

Biochem Biophys Res Commun. 2023 Nov 5:680:211-219. doi: 10.1016/j.bbrc.2023.09.022. Epub 2023 Sep 13.

Authors

Hironori Suzuki¹, Akira Yokoi², Kaname Uno³, Kosuke Yoshida⁴, Masami Kitagawa⁵, Eri Asano-Inami⁶, Seiko Matsuo⁶, Yukari Nagao⁶, Kazuhiro Suzuki⁶, Kae Nakamura⁷, Masato Yoshihara⁶, Satoshi Tamauchi⁶, Yusuke Shimizu⁶, Yoshiki Ikeda⁶, Nobuhisa Yoshikawa⁶, Hiroaki Kajiyama⁶, Yusuke Yamamoto⁸

Affiliations

¹ Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan.
² Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Institute for Advanced Research, Nagoya University, Nagoya, Japan. Electronic address: ayokoi@med.nagoya-u.ac.jp.
³ Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
⁴ Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Institute for Advanced Research, Nagoya University, Nagoya, Japan; Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan.
⁵ Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁶ Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁷ Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Center for Low-temperature Plasma Sciences, Nagoya University, Nagoya, Japan.
⁸ Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan. Electronic address: yuyamamo@ncc.go.jp.

PMID: 37782986
DOI: 10.1016/j.bbrc.2023.09.022

Abstract

Introduction: Ovarian cancer is the leading cause of death among women with gynecological cancer, and novel treatment options are urgently needed. Extracellular vesicles (EVs), including exosomes, may be one of the most promising therapeutic tools for various diseases. In this study, we aimed to investigate the therapeutic effects of adipose-derived stem cell-derived EVs (ADSC-EVs) on ovarian cancer cell lines.

Materials and methods: ADSCs and the ovarian cancer cell lines SKOV3 and OV90 were used for analysis. ADSC-EVs were isolated through ultracentrifugation and validated using a cryotransmission electron microscope, nanoparticle tracking analysis, and western blotting. Then, the effect of ADSC-EVs on ovarian cancer cells was investigated using IncuCyte and microRNA sequencing. Moreover, the potential functions of miRNAs were evaluated by gain-of function analysis and in silico analysis.

Results: ADSC-EVs suppressed SKOV3 and OV90 cell proliferation. In particular, small EVs (sEVs) from ADSCs exhibited a stronger antitumor effect than ADSC-medium/large EVs (m/lEVs). Comparison of the miRNA profiles between ADSC-sEVs and ADSC-m/lEVs, along with downstream pathway analysis, suggested the involvement of the let-7 family. Overexpression of hsa-let-7b-5p and hsa-let-7e-5p significantly suppressed the proliferation of SKOV3 cells. In silico analysis revealed that four potential target genes of hsa-let-7b-5p and hsa-let-7e-5p were significantly associated with the prognoses of the patients.

Conclusion: ADSC-sEVs had a stronger antitumor effect than ADSC-m/lEVs. Hsa-let-7b-5p and hsa-let-7e-5p, which are highly abundant in ADSC-sEVs, suppressed cell proliferation. These findings may open up new possibilities for therapeutic approaches using ADSC-sEVs.

Keywords: Medium/large extracellular vesicles; Ovarian cancer; Small extracellular vesicles; hsa-let-7b-5p; hsa-let-7e-5p.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Proliferation
Extracellular Vesicles* / metabolism
Female
Humans
MicroRNAs* / genetics
MicroRNAs* / metabolism
Ovarian Neoplasms* / genetics
Ovarian Neoplasms* / therapy
Stem Cells / metabolism

Substances

MicroRNAs