title: Leptin enhances cholangiocarcinoma cell growth.
abstract: Cholangiocarcinoma is a strongly aggressive malignancy with a very poor prognosis. Effective therapeutic strategies are lacking because molecular mechanisms regulating cholangiocarcinoma cell growth are unknown. Furthermore, experimental in vivo animal models useful to study the pathophysiologic mechanisms of malignant cholangiocytes are lacking. Leptin, the hormone regulating caloric homeostasis, which is increased in obese patients, stimulates the growth of several cancers, such as hepatocellular carcinoma. The aim of this study was to define if leptin stimulates cholangiocarcinoma growth. We determined the expression of leptin receptors in normal and malignant human cholangiocytes. Effects on intrahepatic cholangiocarcinoma (HuH-28) cell proliferation, migration, and apoptosis of the in vitro exposure to leptin, together with the intracellular pathways, were then studied. Moreover, cholangiocarcinoma was experimentally induced in obese fa/fa Zucker rats, a genetically established animal species with faulty leptin receptors, and in their littermates by chronic feeding with thioacetamide, a potent carcinogen. After 24 weeks, the effect of leptin on cholangiocarcinoma development and growth was assessed. Normal and malignant human cholangiocytes express leptin receptors. Leptin increased the proliferation and the metastatic potential of cholangiocarcinoma cells in vitro through a signal transducers and activators of transcription 3-dependent activation of extracellular signal-regulated kinase 1/2. Leptin increased the growth and migration, and was antiapoptotic for cholangiocarcinoma cells. Moreover, the loss of leptin function reduced the development and the growth of cholangiocarcinoma. The experimental carcinogenesis model induced by thioacetamide administration is a valid and reproducible method to study cholangiocarcinoma pathobiology. Modulation of the leptin-mediated signal could be considered a valid tool for the prevention and treatment of cholangiocarcinoma.
authors.affiliation: Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy. giammarcofava@hotmail.com
authors.forename: Giammarco
authors.initials: G
authors.lastname: Fava
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
authors.forename: Chiara
authors.initials: C
authors.lastname: Rychlicki
authors.forename: Stefania
authors.initials: S
authors.lastname: Saccomanno
authors.forename: Sharon
authors.initials: S
authors.lastname: DeMorrow
authors.forename: Luciano
authors.initials: L
authors.lastname: Trozzi
authors.forename: Cinzia
authors.initials: C
authors.lastname: Candelaresi
authors.forename: Julie
authors.initials: J
authors.lastname: Venter
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Sario
authors.forename: Marco
authors.initials: M
authors.lastname: Marzioni
authors.forename: Italo
authors.initials: I
authors.lastname: Bearzi
authors.forename: Shannon
authors.initials: S
authors.lastname: Glaser
authors.forename: Domenico
authors.initials: D
authors.lastname: Alvaro
authors.forename: Luca
authors.initials: L
authors.lastname: Marucci
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
authors.forename: Gianluca
authors.initials: G
authors.lastname: Svegliati-Baroni
authors.forename: Antonio
authors.initials: A
authors.lastname: Benedetti
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology*; D001652:Bile Ducts / Q000166:cytology / Q000378:metabolism; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D020738:Leptin / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D054411:Receptors, Leptin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013853:Thioacetamide / Q000494:pharmacology
chemical_list: D020738:Leptin; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013853:Thioacetamide; D053612:Janus Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases