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      miRNA-target network reveals miR-124as a key miRNA contributing to clear cell renal cell carcinoma aggressive behaviour by targeting CAV1 and FLOT1

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          Abstract

          Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor with frequent metastatic rate and poor survival. Integrated analyses allow understanding the interplay between different levels of molecular alterations.

          We integrated miRNA and gene expression data from 458 ccRCC and 254 normal kidney specimens to construct a miRNA-target interaction network.

          We identified the downregulated miR-124-3p, -30a-5p and -200c-3p as the most influential miRNAs in RCC pathogenesis.miR-124-3p and miR-200c-3p expression showed association with patient survival, miR-30a-5p was downregulated in metastases compared to primary tumors. We used an independent set of 87 matched samples for validation. We confirmed the functional impact of these miRNAs by in vitro assays. Restoration of these miRNAs reduced migration, invasion and proliferation. miR-124-3p decreased the S phase of cell cycle, as well. We compared transcriptome profiling before and after miRNA overexpression, and validated CAV1 and FLOT1 as miR-124-3p targets. Patients with higher CAV1 and FLOT1 had lower miR-124-3p expression and shorter overall survival.

          We hypothesize that these three miRNAs are fundamental contributing to ccRCC aggressive/metastatic behavior; and miR-124-3p especially has a key role through regulating CAV1 and FLOT1 expression. Restoration of the levels of these miRNAs could be considered as a potential therapeutic strategy for ccRCC.

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          Most cited references41

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          Renal cell carcinoma.

          Renal Cell Carcinoma (RCC) has the highest mortality rate of the genitourinary cancers and the incidence of RCC has risen steadily. If detected early, RCC is curable by surgery although a minority are at risk of recurrence. Increasing incidental detection and an ageing population has led to active surveillance as an option for patients with small renal masses. RCC is heterogeneous and comprises several histological cell types with different genetics, biology and behavior. The identification of the genes predisposing to inherited syndromes with RCC has provided much of our knowledge of the molecular basis of early sporadic RCC. Many of the oncogenes and tumor suppressor genes that are mutated leading to pathway dysregulation in RCC remain to be elucidated. Global studies of copy number, gene sequencing, gene expression, miRNA expression and gene methylation in primary RCC will lead towards this goal. The natural history of RCC indicated by candidate precursor lesions, multifocal or bilateral disease, growth rate of small renal masses under surveillance, and high risk populations provide insight into the behavior of this disease. The use of molecular markers for early detection and prognosis merits more attention with ongoing advances in omics technologies. This review focuses on early RCC, that is disease confined within the renal capsule.
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            A requirement for caveolin-1 and associated kinase Fyn in integrin signaling and anchorage-dependent cell growth.

            Caveolin-1 functions as a membrane adaptor to link the integrin alpha subunit to the tyrosine kinase Fyn. Upon integrin ligation, Fyn is activated and binds, via its SH3 domain, to Shc. Shc is subsequently phosphorylated at tyrosine 317 and recruits Grb2. This sequence of events is necessary to couple integrins to the Ras-ERK pathway and promote cell cycle progression. These findings reveal an unexpected function of caveolin-1 and Fyn in integrin signaling and anchorage-dependent cell growth.
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              Methylation-mediated silencing of the miR-124 genes facilitates pancreatic cancer progression and metastasis by targeting Rac1.

              Previous studies have demonstrated that microRNA (miRNA) expression is altered in human cancer. However, the molecular mechanism underlying these changes in miRNA expression remains unclear. In this study, we investigated the epigenetic modification of miR-124 genes and the potential function of miR-124 in pancreatic cancer. Using pyrosequencing analysis, we found that miR-124 genes (including miR-124-1, miR-124-2 and miR-124-3) are highly methylated in pancreatic cancer tissues compared with in non-cancerous tissues. Hypermethylation mediated the silencing of miR-124, which was a frequent event in pancreatic duct adenocarcinoma (PDAC). Furthermore, miR-124 downregulation was significantly associated with worse survival of PDAC patients. Functional studies showed that miR-124 inhibited cell proliferation, invasion and metastasis. Furthermore, we characterized Rac1 as a direct target of miR-124, and miR-124 interacted with the 3'-untranslated region of Rac1, which we showed to be a putative tumor promoter in pancreatic cancer. Thus, the miR-124-mediated downregulation of Rac1 led to the inactivation of the MKK4-JNK-c-Jun pathway. Therefore, our study demonstrates that miR-124 is a tumor suppressor miRNA that is epigenetically silenced in pancreatic cancer. Our findings suggest a previously unidentified molecular mechanism involved in the progression and metastasis of pancreatic cancer.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                20 May 2015
                14 April 2015
                : 6
                : 14
                : 12543-12557
                Affiliations
                1 Department of Laboratory Medicine and The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Canada
                2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
                3 Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
                4 HAS-SE “Lendulet” Hereditary Endocrine Tumors Research Group, Hungarian Academy of Sciences, Hungary
                Author notes
                Correspondence to: George M. Yousef, yousefg@ 123456smh.ca
                Article
                10.18632/oncotarget.3815
                4494957
                26002553
                6d4e1bba-7040-4401-9a0e-63f4c816fae9
                Copyright: © 2015 Butz et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 18 February 2015
                : 11 March 2015
                Categories
                Research Paper

                Oncology & Radiotherapy
                renal cell carcinoma,mir-124-3p,integrated analysis,cav1,flot1
                Oncology & Radiotherapy
                renal cell carcinoma, mir-124-3p, integrated analysis, cav1, flot1

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