title: MicroRNA-155 Controls Exosome Synthesis and Promotes Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma.
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.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Mikamori
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.
authors.forename: Daisaku
authors.initials: D
authors.lastname: Yamada
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Eguchi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Hasegawa
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kishimoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Tomimaru
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Asaoka
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Noda
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wada
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawamoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.
authors.forename: Kunihito
authors.initials: K
authors.lastname: Gotoh
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.|Department of Surgery, Kansai Rosai Hospital, Inabasou 3-1-69, Amagasaki, Hyogo, 660-8511, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takeda
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.|Department of Surgery, Osaka Police Hospital, Tennoji-ku Kitayamacho 10-31, Osaka, 543-0035, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tanemura
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000648:ultrastructure; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000648:ultrastructure; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D042282:Microdissection; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000648:ultrastructure; D011379:Prognosis; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D003841:Deoxycytidine; D000093542:Gemcitabine