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FEBS Open Bio. 2021 Dec;11(12):3276-3292. doi: 10.1002/2211-5463.13294. Epub 2021 Sep 22.

Extracellular RNA transfer from non-malignant human cholangiocytes can promote cholangiocarcinoma growth.

FEBS open bio

Yu Ota, Kenji Takahashi, Shin Otake, Yosui Tamaki, Mitsuyoshi Okada, Irene Yan, Kazunobu Aso, Satoshi Fujii, Tushar Patel, Masakazu Haneda

Affiliations

  1. Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan.
  2. Departments of Transplantation and Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
  3. Department of Laboratory Medicine, Asahikawa Medical University, Japan.

PMID: 34510808 PMCID: PMC8634862 DOI: 10.1002/2211-5463.13294

Abstract

Extracellular vesicles (EV) within the cellular secretome are emerging as modulators of pathological processes involved in tumor growth through their ability to transfer donor-derived RNA into recipient cells. While the effects of tumor and stromal cell EVs within the tumor microenvironment have been studied, less is known about the contributions of normal, nontransformed cells. We examined the impact of EVs within the cellular secretome from nonmalignant cells on transformed cell growth and behavior in cholangiocarcinoma cells. These effects were enhanced in the presence of the pro-fibrogenic mediator TGF-β. We identified miR-195 as a TGF-β responsive miRNA in normal cells that can be transferred via EV to tumor cells and regulate cell growth, invasion, and migration. The effects of miR-195 involve modulation of the epithelial-mesenchymal transition through direct effects on the transcription factor Snail. These studies provide in vitro and in vivo evidence for the impact of normal cellular secretome on transformed cell growth, show the importance of EV RNA transfer, and identify mechanisms of EV-mediated transfer of miRNA as a contributor to tumor development, which may provide new therapeutic opportunities for targeting human cholangiocarcinoma.

© 2021 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Keywords: epithelial-mesenchymal transition; extracellular vesicles; microRNA; secretome; tumor microenvironment

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