Inhibition of the apelin/apelin receptor axis decreases cholangiocarcinoma growth. (1st February 2017)

• Record Type: Journal Article
• Authors: Hall, Chad; Ehrlich, Laurent; Venter, Julie; O'Brien, April; White, Tori; Zhou, Tianhao; Dang, Tien; Meng, Fanyin; Invernizzi, Pietro; Bernuzzi, Francesca; Alpini, Gianfranco; Lairmore, Terry C.; Glaser, Shannon
• Is Part Of: Cancer letters. Volume 386(2017)
• Page Start: 179
• Page End: 188
• Publication Date: 2017-02-01
• Subjects: Apelin -- Apelin receptor -- Cholangiocarcinoma -- Biliary epithelium -- Proliferation; APLNR apelin receptor -- Ang 1 angiopoietin 1 -- Ang 2 angiopoietin 2 -- AT1 angiotensin-type 1 -- CCA cholangiocarcinoma -- CK-19 cytokeratin-19 -- EMT epithelial-mesenchymal transition -- ERK extracellular signal-regulated kinase -- GAPDH glyceraldehyde-3-phosphate dehydrogenase -- HIF hypoxia-inducible factor -- IHC immunohistochemistry -- PBS phosphate buffered saline -- PSC primary sclerosing cholangitis -- VEGF-A vascular endothelial growth factor-A -- VEGF-C vascular endothelial growth factor-C; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2016.11.025
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Purpose: 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. Methods: 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. Results: 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. Conclusion: 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. Highlights: Expression of the apelin/apelin receptor axis is upregulated in cholangiocarcinoma. Inhibition of apelin receptor signaling inhibits cholangiocarcinoma proliferation and angiogenesis. Targeting the apelin receptor axis could provide novel, tumor directed therapies to inhibit cholangiocarcinoma progression.