title: miR-27 is associated with chemoresistance in esophageal cancer through transformation of normal fibroblasts to cancer-associated fibroblasts.
abstract: There is increasing evidence that the expression of microRNA (miRNA) in cancer is associated with chemosensitivity but the mechanism of miRNA-induced chemoresistance has not been fully elucidated. The aim of this study was to examine the role of extracellular miRNA in the response to chemotherapy in esophageal cancer. First, serum expression of miRNAs selected by miRNA array was measured by quantitative reverse transcription-polymerase chain reaction in 68 patients with esophageal cancer who received cisplatin-based chemotherapy to examine the relationship between miRNA expression and response to chemotherapy. The serum expression levels of 18 miRNAs were different between responders and non-responders by miRNA array. Of these, high expression levels of miR-27a/b correlated with poor response to chemotherapy in patients with esophageal cancer. Next, in vitro assays were conducted to investigate the mechanism of miRNA-induced chemoresistance. Although transfection of miR-27a/b to cancer cells had no significant impact on chemosensitivity, esophageal cancer cells cultured in supernatant of miR-27a/b-transfected normal fibroblast showed reduced chemosensitivity to cisplatin, compared with cancer cells cultured in supernatant of normal fibroblast. MiR-27a/b-transfected normal fibroblast showed α-smooth muscle actin (α-SMA) expression, a marker of cancer-associated fibroblasts (CAF) and increased production of transforming growth factor-β (TGF-β). Chemosensitivity recovered after administration of neutralizing antibody of TGF-β to the supernatant transfer experiments. Our results indicated that miR-27a/b is involved in resistance to chemotherapy in esophageal cancer, through miR-27a/b-induced transformation of normal fibroblast into CAF.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita city, Osaka 565-0871, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita city, Osaka 565-0871, Japan hmiyata@gesurg.med.osaka-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyata
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita city, Osaka 565-0871, Japan.
authors.forename: Keijiro
authors.initials: K
authors.lastname: Sugimura
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita city, Osaka 565-0871, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Fukuda
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita city, Osaka 565-0871, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanemura
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita city, Osaka 565-0871, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita city, Osaka 565-0871, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Miyazaki
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita city, Osaka 565-0871, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita city, Osaka 565-0871, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Kurokawa
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita city, Osaka 565-0871, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamasaki
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita city, Osaka 565-0871, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Wada
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita city, Osaka 565-0871, Japan.
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Nakajima
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita city, Osaka 565-0871, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Takiguchi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita city, 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, 2-2 Yamadaoka, Suita city, Osaka 565-0871, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D005347:Fibroblasts / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D012016:Reference Values; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D016212:Transforming Growth Factor beta; D002945:Cisplatin