title: Galectin-9 suppresses cholangiocarcinoma cell proliferation by inducing apoptosis but not cell cycle arrest.
abstract: Cholangiocarcinoma is the most common biliary malignancy and the second most common hepatic malignancy after hepatocellular carcinoma (HCC). Galectin-9 (Gal-9) is a tandem-repeat-type galectin that has recently been shown to exert antiproliferative effects on cancer cells. Therefore, the present study evaluated the effects of Gal-9 on the proliferation of human cholangiocarcinoma cells in vitro as well as the microRNAs (miRNAs) associated with the antitumor effects of Gal-9. Gal-9 suppressed the proliferation of cholangiocarcinoma cell lines in vitro and the growth of human cholangiocarcinoma cell xenografts in nude mice. Our data further revealed that Gal-9 increased caspase‑cleaved keratin 18 (CCK18) levels, and the expression of cytochrome c increased in Gal-9-treated cholangiocarcinoma cell lines. These data suggested that Gal-9 induced cholangiocarcinoma cell apoptosis via the intrinsic apoptosis pathway mediated by caspase-dependent or -independent pathways. In addition, Gal-9 reduced the phosphorylation of the epidermal growth factor receptor (EGFR), insulin-like growth factor and insulin-like growth factor-1 receptor (IGF-1R), hepatocyte growth factor receptor and fibroblast growth factor receptor 3 (FGFR3). These findings suggest that Gal-9 can be a candidate of therapeutic target in the treatment of cholangiocarcinoma.
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Kiyoyuki
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Asahiro
authors.initials: A
authors.lastname: Morishita
authors.affiliation: Life Science Research Center, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Iwama
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Okura
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Fujihara
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujimori
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Kiyohito
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kamada
authors.affiliation: Department of Immunology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niki
authors.affiliation: Department of Immunology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Mitsuomi
authors.initials: M
authors.lastname: Hirashima
authors.affiliation: Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Okano
authors.affiliation: Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masaki
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000473:pathology; D045304:Cytochromes c / Q000096:biosynthesis; D066246:ErbB Receptors / Q000096:biosynthesis; D005346:Fibroblast Growth Factors / Q000096:biosynthesis; D037161:Galectins / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053538:Keratin-18 / Q000096:biosynthesis; D051379:Mice; D023041:Xenograft Model Antitumor Assays
chemical_list: D037161:Galectins; C488421:KRT18 protein, human; D053538:Keratin-18; C105032:LGALS9 protein, human; D005346:Fibroblast Growth Factors; D045304:Cytochromes c; C512478:EGFR protein, human; D066246:ErbB Receptors