Τίτλος:
An integrated genomic analysis of papillary renal cell carcinoma type 1 uncovers the role of focal adhesion and extracellular matrix pathways
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2015 Federation of European Biochemical Societies.
Συγγραφείς:
Wala, S.J.
Karamchandani, J.R.
Saleeb, R.
Evans, A.
Ding, Q.
Ibrahim, R.
Jewett, M.
Pasic, M.
Finelli, A.
Pace, K.
Lianidou, E.
Yousef, G.M.
Περιοδικό:
Molecular Oncology
Λέξεις-κλειδιά:
beta integrin; caveolin 2; complementary DNA; mammalian target of rapamycin; microRNA; microRNA 199a 3p; RNA; unclassified drug; microRNA, 3' untranslated region; Article; cell culture; cell proliferation assay; controlled study; extracellular matrix; focal adhesion; gene expression; genetic transfection; genomics; human; human cell; human tissue; kidney carcinoma; kidney parenchyma; luciferase assay; major clinical study; papillary carcinoma; papillary renal cell carcinoma; priority journal; protein expression; proto oncogene; real time polymerase chain reaction; reverse transcription polymerase chain reaction; Western blotting; cell proliferation; classification; extracellular matrix; focal adhesion; gene expression profiling; gene expression regulation; genetics; genomics; kidney; kidney carcinoma; kidney tumor; metabolism; pathology; physiology; procedures; signal transduction; system analysis; tumor cell culture, Carcinoma, Renal Cell; Cell Proliferation; Extracellular Matrix; Focal Adhesions; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genomics; Humans; Kidney; Kidney Neoplasms; MicroRNAs; Signal Transduction; Systems Integration; Tumor Cells, Cultured
DOI:
10.1016/j.molonc.2015.04.007
