PMID- 26051997 OWN - NLM STAT- MEDLINE DCOM- 20160815 LR - 20220311 IS - 1878-0261 (Electronic) IS - 1574-7891 (Print) IS - 1574-7891 (Linking) VI - 9 IP - 8 DP - 2015 Oct TI - An integrated genomic analysis of papillary renal cell carcinoma type 1 uncovers the role of focal adhesion and extracellular matrix pathways. PG - 1667-77 LID - S1574-7891(15)00095-2 [pii] LID - 10.1016/j.molonc.2015.04.007 [doi] AB - Papillary renal cell carcinoma (pRCC) is the second most common RCC subtype and can be further classified as type 1 (pRCC1) or 2 (pRCC2). There is currently minimal understanding of pRCC1 pathogenesis, and treatment decisions are mostly empirical. The aim of this study was to identify biological pathways that are involved in pRCC1 pathogenesis using an integrated genomic approach. By microarray analysis, we identified a number of significantly dysregulated genes and microRNAs (miRNAs) that were unique to pRCC1. Integrated bioinformatics analyses showed enrichment of the focal adhesion and extracellular matrix (ECM) pathways. We experimentally validated that many members of these pathways are dysregulated in pRCC1. We identified and experimentally validated the downregulation of miR-199a-3p in pRCC1. Using cell line models, we showed that miR-199a-3p plays an important role in pRCC1 pathogenesis. Gain of function experiments showed that miR-199a-3p overexpression significantly decreased cell proliferation (p = 0.013). We also provide evidence that miR-199a-3p regulates the expression of genes linked to the focal adhesion and ECM pathways, such as caveolin 2 (CAV2), integrin beta 8 (ITGB8), MET proto-oncogene and mammalian target of rapamycin (MTOR). Using a luciferase reporter assay, we further provide evidence that miR-199a-3p overexpression decreases the expression of MET and MTOR. Using an integrated gene/miRNA approach, we provide evidence linking miRNAs to the focal adhesion and ECM pathways in pRCC1 pathogenesis. This novel information can contribute to the development of effective targeted therapies for pRCC1, for which there is none currently available in the clinic. CI - Copyright (c) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. FAU - Wala, Samantha Jane AU - Wala SJ AD - The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. Electronic address: Samantha.wala@gmail.com. FAU - Karamchandani, Jason Raj AU - Karamchandani JR AD - Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. Electronic address: jkaramch@gmail.com. FAU - Saleeb, Rola AU - Saleeb R AD - Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. Electronic address: rola.saleeb@mail.utoronto.ca. FAU - Evans, Andrew AU - Evans A AD - Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada; Department of Pathology, Toronto General Hospital, Toronto, Ontario, Canada. Electronic address: andrew.evans@uhn.on.ca. FAU - Ding, Qiang AU - Ding Q AD - The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada. Electronic address: DingQ@smh.ca. FAU - Ibrahim, Rania AU - Ibrahim R AD - The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada. Electronic address: IbrahimR@smh.ca. FAU - Jewett, Michael AU - Jewett M AD - Department of Surgery, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Electronic address: m.jewett@utoronto.ca. FAU - Pasic, Maria AU - Pasic M AD - Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada; Department of Laboratory Medicine, St. Joseph's Health Centre, 30 Queensway, Ontario M6R 1B5, Canada. Electronic address: pasicm@stjoe.on.ca. FAU - Finelli, Antonio AU - Finelli A AD - Department of Surgery, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Electronic address: antonio.finelli@uhn.ca. FAU - Pace, Kenneth AU - Pace K AD - Department of Surgery, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada. Electronic address: pacek@smh.ca. FAU - Lianidou, Evi AU - Lianidou E AD - Laboratory of Analytical Chemistry, Department of Chemistry, University of Athens, 15771 Athens, Greece. Electronic address: lianidou@chem.uoa.gr. FAU - Yousef, George Makram AU - Yousef GM AD - The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. Electronic address: yousefg@smh.ca. LA - eng GR - MOP 119606/Canadian Institutes of Health Research/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150514 PL - United States TA - Mol Oncol JT - Molecular oncology JID - 101308230 RN - 0 (MAS1 protein, human) RN - 0 (MicroRNAs) RN - 0 (Proto-Oncogene Mas) SB - IM MH - Carcinoma, Renal Cell/classification/*genetics/pathology MH - Cell Proliferation/genetics MH - Extracellular Matrix/*physiology MH - Focal Adhesions/*physiology MH - Gene Expression Profiling MH - Gene Expression Regulation, Neoplastic MH - Genomics/*methods MH - Humans MH - Kidney/metabolism/pathology MH - Kidney Neoplasms/classification/*genetics/pathology MH - MicroRNAs/genetics MH - Proto-Oncogene Mas MH - Signal Transduction/physiology MH - Systems Integration MH - Tumor Cells, Cultured PMC - PMC5528794 OTO - NOTNLM OT - Extracellular matrix OT - Focal adhesion OT - Genetics OT - MET OT - Papillary renal cell carcinoma OT - miR-199a-3p EDAT- 2015/06/09 06:00 MHDA- 2016/08/16 06:00 PMCR- 2015/10/01 CRDT- 2015/06/09 06:00 PHST- 2014/12/23 00:00 [received] PHST- 2015/04/18 00:00 [revised] PHST- 2015/04/20 00:00 [accepted] PHST- 2015/06/09 06:00 [entrez] PHST- 2015/06/09 06:00 [pubmed] PHST- 2016/08/16 06:00 [medline] PHST- 2015/10/01 00:00 [pmc-release] AID - S1574-7891(15)00095-2 [pii] AID - MOL22015981667 [pii] AID - 10.1016/j.molonc.2015.04.007 [doi] PST - ppublish SO - Mol Oncol. 2015 Oct;9(8):1667-77. doi: 10.1016/j.molonc.2015.04.007. Epub 2015 May 14.