Chad Hall1, Laurent Ehrlich2, Julie Venter3, April O'Brien4, Tori White4, Tianhao Zhou5, Tien Dang6, Fanyin Meng6, Pietro Invernizzi7, Francesca Bernuzzi7, Gianfranco Alpini8, Terry C Lairmore1, Shannon Glaser9. 1. Scott & White Medical Center, Department of Surgery, Temple, TX 76508, USA. 2. Scott & White Medical Center, Department of Medicine, Temple, TX 76508, USA; Scott & White Medical Center, Department of Surgery, Temple, TX 76508, USA. 3. Scott & White Medical Center, Department of Medicine, Temple, TX 76508, USA. 4. Research, Central Texas Veterans Health Care System, Temple, TX 76504, USA. 5. Scott & White Medical Center, Department of Medicine, Temple, TX 76508, USA; Texas A&M University Health Science Center, Temple, TX 76504, USA. 6. Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, TX 76504, USA. 7. Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy. 8. 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. 9. 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.
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.
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/APLNRaxis decreases tumor growth in our xenograft model. Targeting APLNR signaling has the potential to serve as a novel, tumor directed therapy for CCA.
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