PMID- 29044946 OWN - NLM STAT- MEDLINE DCOM- 20190422 LR - 20190422 IS - 1582-4934 (Electronic) IS - 1582-1838 (Print) IS - 1582-1838 (Linking) VI - 22 IP - 2 DP - 2018 Feb TI - Aquaporin-1 inhibition reduces metastatic formation in a mouse model of melanoma. PG - 904-912 LID - 10.1111/jcmm.13378 [doi] AB - Aquaporin-1 (AQP1) is a proangiogenic water channel protein promoting endothelial cell migration. We previously reported that AQP1 silencing by RNA interference reduces angiogenesis-dependent primary tumour growth in a mouse model of melanoma. In this study, we tested the hypothesis that AQP1 inhibition also affects animal survival and lung nodule formation. Melanoma was induced by injecting B16F10 cells into the back of C57BL6J mice. Intratumoural injection of AQP1 siRNA and CTRL siRNA was performed 10 days after tumour cell implantation. Lung nodule formation was analysed after the death of the mice. Western blot was used to quantify HIF-1alpha, caspase-3 (CASP3) and metalloproteinase-2 (MMP2) protein levels. We found that AQP1 knock-down (KD) strongly inhibited metastatic lung nodule formation. Moreover, AQP1 siRNA-treated mice showed a twofold survival advantage compared to mice receiving CTRL siRNAs. The reduced AQP1-dependent tumour angiogenesis caused a hypoxic condition, evaluated by HIF-1alpha significant increase, in turn causing an increased level of apoptosis in AQP1 KD tumours, assessed by CASP3 quantification and DNA fragmentation. Importantly, a decreased level of MMP2 after AQP1 KD indicated a decreased activity against extracellular matrix associated with reduced vascularization and metastatic formation. In conclusion, these findings highlight an additional role for AQP1 as an important determinant of tumour dissemination by facilitating tumour cell extravasation and metastatic formation. This study adds knowledge on the role played by AQP1 in tumour biology and supports the view of AQP1 as a potential drug target for cancer therapy. CI - (c) 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. FAU - Simone, Laura AU - Simone L AD - IRCCS Casa Sollievo della Sofferenza, Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), San Giovanni Rotondo, FG, Italy. AD - Department of Bioscience, Biotechnologies and Biopharmaceutics, Centre of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, BA, Italy. FAU - Gargano, Concetta Domenica AU - Gargano CD AD - Department of Bioscience, Biotechnologies and Biopharmaceutics, Centre of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, BA, Italy. FAU - Pisani, Francesco AU - Pisani F AD - Department of Bioscience, Biotechnologies and Biopharmaceutics, Centre of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, BA, Italy. FAU - Cibelli, Antonio AU - Cibelli A AD - Department of Bioscience, Biotechnologies and Biopharmaceutics, Centre of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, BA, Italy. FAU - Mola, Maria Grazia AU - Mola MG AD - Department of Bioscience, Biotechnologies and Biopharmaceutics, Centre of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, BA, Italy. FAU - Frigeri, Antonio AU - Frigeri A AD - School of Medicine, Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari "Aldo Moro", Bari, BA, Italy. AD - Department of Neuroscience, Albert Einstein College of Medicine, Yeshiva University, New York, Bronx, NY, USA. FAU - Svelto, Maria AU - Svelto M AD - Department of Bioscience, Biotechnologies and Biopharmaceutics, Centre of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, BA, Italy. AD - Institute of Biomembranes and Bioenergetics, National Research Council, Bari, BA, Italy. AD - National Institute of Biostructures and Biosystems (INBB), Rome, Italy. FAU - Nicchia, Grazia Paola AU - Nicchia GP AD - Department of Bioscience, Biotechnologies and Biopharmaceutics, Centre of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, BA, Italy. AD - Department of Neuroscience, Albert Einstein College of Medicine, Yeshiva University, New York, Bronx, NY, USA. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171017 PL - England TA - J Cell Mol Med JT - Journal of cellular and molecular medicine JID - 101083777 RN - 0 (RNA, Small Interfering) RN - 146410-94-8 (Aquaporin 1) RN - EC 3.4.22.- (Caspases) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) SB - IM MH - Animals MH - Apoptosis MH - Aquaporin 1/*metabolism MH - Caspases/metabolism MH - Cell Line, Tumor MH - DNA Fragmentation MH - Disease Models, Animal MH - Gene Silencing MH - Lung Neoplasms/pathology/*secondary MH - Male MH - Matrix Metalloproteinase 2/metabolism MH - Melanoma, Experimental/blood supply/*metabolism/*pathology MH - Mice, Inbred C57BL MH - Models, Biological MH - Neovascularization, Pathologic/metabolism/pathology MH - RNA, Small Interfering/metabolism MH - Survival Analysis MH - Time Factors MH - Tumor Hypoxia PMC - PMC5783831 OTO - NOTNLM OT - antiangiogenic therapy OT - apoptosis OT - aquaporin-1 OT - endothelial migration OT - extracellular matrix OT - melanoma OT - metastasis OT - tumour angiogenesis EDAT- 2017/10/19 06:00 MHDA- 2019/04/23 06:00 PMCR- 2018/02/01 CRDT- 2017/10/19 06:00 PHST- 2017/04/05 00:00 [received] PHST- 2017/08/16 00:00 [accepted] PHST- 2017/10/19 06:00 [pubmed] PHST- 2019/04/23 06:00 [medline] PHST- 2017/10/19 06:00 [entrez] PHST- 2018/02/01 00:00 [pmc-release] AID - JCMM13378 [pii] AID - 10.1111/jcmm.13378 [doi] PST - ppublish SO - J Cell Mol Med. 2018 Feb;22(2):904-912. doi: 10.1111/jcmm.13378. Epub 2017 Oct 17.