MicroRNA-155 controls exosome synthesis and promotes gemcitabine resistance in pancreatic ductal adenocarcinoma

Manabu Mikamori, Daisaku Yamada, Hidetoshi Eguchi, Shinichiro Hasegawa, Tomoya Kishimoto, Yoshito Tomimaru, Tadafumi Asaoka, Takehiro Noda, Hiroshi Wada, Koichi Kawamoto, Kunihito Gotoh, Yutaka Takeda, Masahiro Tanemura, Masaki Mori, Yuichiro Doki

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Abstract

The cancer drug gemcitabine (GEM) is a key drug for treating pancreatic ductal adenocarcinoma (PDAC), but PDAC cells develop chemoresistance after long-term administration. Since the tolerance was immediately spread to every PDAC tissue in a patient, it is assumed that some certain efficient mechanisms underlay in the development of chemoresistance. Changes in the levels of particular microRNAs or alterations in intercellular communication play a dominant role in chemoresistance development, and recent data also suggest that exosomes play an important role in this process. In this study, we revealed that the loop conferred chemoresistance in PDAC cells. The loop was as follows; 1, The long-term exposure of GEM increased miR-155 expression in PDAC cells. 2, The increase of miR-155 induced two different functions; exosome secretion and chemoresistance ability via facilitating the anti-apoptotic activity. 3, Exosome deliver the miR-155 into the other PDAC cells and induce the following function. The target therapy to miR-155 or the exosome secretion effectively attenuated the chemoresistance, and these results were validated with both clinical samples and in vivo experiments. This mechanism represents a novel therapeutic target in GEM treatment to PDAC.

Original languageEnglish
Article number42339
JournalScientific reports
Volume7
DOIs
Publication statusPublished - Feb 15 2017

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gemcitabine
Exosomes
MicroRNAs
Adenocarcinoma
Pharmaceutical Preparations
Therapeutics

All Science Journal Classification (ASJC) codes

  • General

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Mikamori, M., Yamada, D., Eguchi, H., Hasegawa, S., Kishimoto, T., Tomimaru, Y., ... Doki, Y. (2017). MicroRNA-155 controls exosome synthesis and promotes gemcitabine resistance in pancreatic ductal adenocarcinoma. Scientific reports, 7, [42339]. https://doi.org/10.1038/srep42339

MicroRNA-155 controls exosome synthesis and promotes gemcitabine resistance in pancreatic ductal adenocarcinoma. / Mikamori, Manabu; Yamada, Daisaku; Eguchi, Hidetoshi; Hasegawa, Shinichiro; Kishimoto, Tomoya; Tomimaru, Yoshito; Asaoka, Tadafumi; Noda, Takehiro; Wada, Hiroshi; Kawamoto, Koichi; Gotoh, Kunihito; Takeda, Yutaka; Tanemura, Masahiro; Mori, Masaki; Doki, Yuichiro.

In: Scientific reports, Vol. 7, 42339, 15.02.2017.

Research output: Contribution to journalArticle

Mikamori, M, Yamada, D, Eguchi, H, Hasegawa, S, Kishimoto, T, Tomimaru, Y, Asaoka, T, Noda, T, Wada, H, Kawamoto, K, Gotoh, K, Takeda, Y, Tanemura, M, Mori, M & Doki, Y 2017, 'MicroRNA-155 controls exosome synthesis and promotes gemcitabine resistance in pancreatic ductal adenocarcinoma', Scientific reports, vol. 7, 42339. https://doi.org/10.1038/srep42339
Mikamori, Manabu ; Yamada, Daisaku ; Eguchi, Hidetoshi ; Hasegawa, Shinichiro ; Kishimoto, Tomoya ; Tomimaru, Yoshito ; Asaoka, Tadafumi ; Noda, Takehiro ; Wada, Hiroshi ; Kawamoto, Koichi ; Gotoh, Kunihito ; Takeda, Yutaka ; Tanemura, Masahiro ; Mori, Masaki ; Doki, Yuichiro. / MicroRNA-155 controls exosome synthesis and promotes gemcitabine resistance in pancreatic ductal adenocarcinoma. In: Scientific reports. 2017 ; Vol. 7.
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