title: Inhibition of the apelin/apelin receptor axis decreases cholangiocarcinoma growth.
abstract: Cholangiocarcinoma (CCA) is a malignancy of the biliary epithelium that is associated with low five-year survival. The apelin receptor (APLNR), which is activated by the apelin peptide, has not been studied in CCA. The purpose of this study is to determine if inhibition of the apelin/APLNR axis can inhibit CCA growth.
  
  
  
  Immunohistochemistry, rtPCR, immunofluorescence, flow cytometry, and ELISA was used to measure APLNR expression in human CCA cells and tissues. Mz-ChA-1 cells were treated with increasing concentrations of apelin and ML221, an APLNR antagonist. Expression of proliferative and angiogenic genes were measured via rtPCR. In vivo, Mz-ChA-1 cells were injected into the flanks of nu/nu mice, which were treated with ML221 (150 μg/kg) via tail vein injection.
  
  
  
  Expression of the apelin/APLNR axis was increased in CCA. In vitro, CCA proliferation and angiogenesis was inhibited by ML221 treatment. ML221 treatment significantly decreased tumor growth in nu/nu mice.
  
  
  
  The apelin/APLNR axis regulates CCA proliferation and angiogenesis. Inhibition of the apelin/APLNR axis decreases tumor growth in our xenograft model. Targeting APLNR signaling has the potential to serve as a novel, tumor directed therapy for CCA.
authors.affiliation: Scott & White Medical Center, Department of Surgery, Temple, TX 76508, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Hall
authors.affiliation: Scott & White Medical Center, Department of Medicine, Temple, TX 76508, USA; Scott & White Medical Center, Department of Surgery, Temple, TX 76508, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Ehrlich
authors.affiliation: Scott & White Medical Center, Department of Medicine, Temple, TX 76508, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Venter
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, TX 76504, USA.
authors.forename: April
authors.initials: A
authors.lastname: O'Brien
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, TX 76504, USA.
authors.forename: Tori
authors.initials: T
authors.lastname: White
authors.affiliation: Scott & White Medical Center, Department of Medicine, Temple, TX 76508, USA; Texas A&M University Health Science Center, Temple, TX 76504, USA.
authors.forename: Tianhao
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, TX 76504, USA.
authors.forename: Tien
authors.initials: T
authors.lastname: Dang
authors.affiliation: Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, TX 76504, USA.
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.affiliation: Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.affiliation: Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bernuzzi
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, TX 76504, USA; Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, TX 76504, USA; Scott & White Medical Center, Department of Medicine, Temple, TX 76508, USA; Scott & White Medical Center, Department of Surgery, Temple, TX 76508, USA.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
authors.affiliation: Scott & White Medical Center, Department of Surgery, Temple, TX 76508, USA.
authors.forename: Terry C
authors.initials: TC
authors.lastname: Lairmore
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, TX 76504, USA; Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, TX 76504, USA; Scott & White Medical Center, Department of Medicine, Temple, TX 76508, USA. Electronic address: sglaser@medicine.tamhsc.edu.
authors.forename: Shannon
authors.initials: S
authors.lastname: Glaser
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D009579:Nitrobenzoates / Q000494:pharmacology*; D011714:Pyrans / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C578927:4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate; C115436:APLN protein, human; C104575:APLNR protein, human; D020533:Angiogenesis Inhibitors; D000073861:Apelin; D000075244:Apelin Receptors; D036341:Intercellular Signaling Peptides and Proteins; D009579:Nitrobenzoates; D011714:Pyrans; D043562:Receptors, G-Protein-Coupled
keywords: Apelin; Apelin receptor; Biliary epithelium; Cholangiocarcinoma; Proliferation