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      Cooperative Effect of miR-141-3p and miR-145-5p in the Regulation of Targets in Clear Cell Renal Cell Carcinoma

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          Abstract

          Background

          Due to the poor prognosis for advanced renal cell carcinoma (RCC), there is an urgent need for new therapeutic targets and for prognostic markers to identify high risk tumors. MicroRNAs (miRNAs) are frequently dysregulated in tumors, play a crucial role during carcinogenesis and therefore might be promising new biomarkers. In previous studies, we identified miR-141-3p and miR-145-5p to be downregulated in clear cell RCC (ccRCC). Our objective was to investigate the functional association of these miRNAs, focusing on the cooperative regulation of new specific targets and their role in ccRCC progression.

          Methods

          The effect of miR-141-3p and miR-145-5p on cell migration was examined by overexpression in 786-O cells. New targets of both miRNAs were identified by miRWalk, validated in 786-O and ACHN cells and additionally characterized in ccRCC tissue on mRNA and protein level.

          Results

          In functional analysis, a tumor suppressive effect of miR-141-3p and miR-145-5p by decreasing migration and invasion of RCC cells could be shown. Furthermore, co-overexpression of the miRNAs seemed to result in an increased inhibition of cell migration. Both miRNAs were recognized as post-transcriptional regulators of the targets EAPP, HS6ST2, LOX, TGFB2 and VRK2. Additionally, they showed a cooperative effect again as demonstrated by a significantly increased inhibition of HS6ST2 and LOX expression after simultaneous overexpression of both miRNAs. In ccRCC tissue, LOX mRNA expression was strongly increased compared to normal tissue, allowing also to distinguish between non-metastatic and already metastasized primary tumors. Finally, in subsequent tissue microarray analysis LOX protein expression showed a prognostic relevance for the overall survival of ccRCC patients.

          Conclusion

          These results illustrate a jointly strengthening effect of the dysregulated miR-141-3p and miR-145-5p in various tumor associated processes. Focusing on the cooperative effect of miRNAs provides new opportunities for the development of therapeutic strategies and offers novel prognostic and diagnostic capabilities.

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          Most cited references60

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          Prognostic significance of morphologic parameters in renal cell carcinoma.

          Susan A. Fuhrman, Larry C Lasky, Catherine Limas (1982)
          The prognostic significance of morphologic parameters was evaluated in 103 patients with renal cell carcinoma diagnosed during 1961--1974. Pathologic material was classified as to pathologic stage, tumor size, cell arrangement, cell type and nuclear grade. Four nuclear grades (1--4) were defined in order of increasing nuclear size, irregularity and nucleolar prominence. Nuclear grade was more effective than each of the other parameters in predicting development of distant metastasis following nephrectomy. Among 45 patients who presented in Stage I, tumors classified as nuclear grade 1 did not metastasize for at least 5 years, whereas 50% of the higher grade tumors did so. Moreover, among Stage I tumors there was a significant difference in subsequent metastatic rate between nuclear grades 1 and 2. There was an apparent positive relationship between cell type and metastatic rate; clear cell tumors were less aggressive than predominantly granular cell tumors (metastatic rate 38% versus 71%). This relationship in part a function of the nuclear grade: only 5% of grade 3 and 4 tumors consisted of clear cells, whereas such high grades were seen in 57% of granular cell tumors. The size of the primary correlated well with the stage at the time of surgery. However, with the exception of extremely large and small tumors, the size was not useful in predicting the subsequent course of patients treated for Stage I tumors. Nuclear grade was the most significant prognostic criterion for the outcome of Stage I renal cell carcinoma.
          Article 0 comments Cited 470 times – based on 0 reviews     Review now
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            Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell.

            Herbert M Kagan, Wande Li (2003)
            Lysyl oxidase (LO) plays a critical role in the formation and repair of the extracellular matrix (ECM) by oxidizing lysine residues in elastin and collagen, thereby initiating the formation of covalent crosslinkages which stabilize these fibrous proteins. Its catalytic activity depends upon both its copper cofactor and a unique carbonyl cofactor and has been shown to extend to a variety of basic globular proteins, including histone H1. Although the three-dimensional structure of LO has yet to be determined, the present treatise offers hypotheses based upon its primary sequence, which may underlie the prominent electrostatic component of its unusual substrate specificity as well as the catalysis-suppressing function of the propeptide domain of prolysyl oxidase. Recent studies have demonstrated that LO appears to function within the cell in a manner, which strongly modifies cellular activity. Newly discovered LO-like proteins also likely play unique roles in biology. Copyright 2002 Wiley-Liss, Inc.
            Article 0 comments Cited 223 times – based on 0 reviews     Review now
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              miR-145, miR-133a and miR-133b: Tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma.

              Masayuki Kano, Naohiko Seki, Naoko Kikkawa … (2010)
              MicroRNAs (miRNAs), noncoding RNAs 21-25 nucleotides in length, regulate gene expression primarily at the posttranscriptional level. Growing evidence suggests that miRNAs are aberrantly expressed in many human cancers, and that they play significant roles in carcinogenesis and cancer progression. A search for miRNAs with a tumor-suppressive function in esophageal squamous cell carcinoma (ESCC) was performed using the miRNA expression signatures obtained from ESCC clinical specimens. A subset of 15 miRNAs was significantly downregulated in ESCC. A comparison of miRNA signatures from ESCC and our previous report identified 4 miRNAs that are downregulated in common (miR-145, miR-30a-3p, miR-133a and miR-133b), suggesting that these miRNAs are candidate tumor suppressors. Gain-of-function analysis revealed that 3 transfectants (miR-145, miR-133a and miR-133b) inhibit cell proliferation and cell invasion in ESCC cells. These miRNAs (miR-145, miR-133a and miR-133b), which have conserved sequences in the 3'UTR of FSCN1 (actin-binding protein, Fascin homolog 1), inhibited FSCN1 expression. The signal from a luciferase reporter assay was significantly decreased at 2 miR-145 target sites and 1 miR-133a/b site, suggesting both miRNAs directly regulate FSCN1. An FSCN1 loss-of-function assay found significant cell growth and invasion inhibition, implying an FSCN1 is associated with ESCC carcinogenesis. The identification of tumor-suppressive miRNAs, miR-145, miR-133a and miR-133b, directly control oncogenic FSCN1 gene. These signal pathways of ESCC could provide new insights into potential mechanisms of ESCC carcinogenesis. Copyright © 2010 UICC.
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                Author and article information

                Contributors
                Hiromu Suzuki: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 23 June 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 6
                Electronic Location Identifier: e0157801
                Affiliations
                [1 ]Department of Urology, Charité - Universitätsmedizin Berlin, Berlin, Germany
                [2 ]Berlin Institute for Urologic Research, Berlin, Germany
                [3 ]Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
                Sapporo Medical University, JAPAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JL KJ. Performed the experiments: JL. Analyzed the data: JL EK HAM. Contributed reagents/materials/analysis tools: JB. Wrote the paper: JL KJ AR.

                Article
                Publisher ID: PONE-D-16-12204
                DOI: 10.1371/journal.pone.0157801
                PMC ID: 4919070
                PubMed ID: 27336447
                SO-VID: a91e1e97-4f1d-4730-9787-71225f73da2f
                Copyright © © 2016 Liep et al
                License:

                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
                Date received : 24 March 2016
                Date accepted : 4 June 2016
                Page count
                Figures: 7, Tables: 4, Pages: 21
                Funding
                Funded by: Foundation for Urologic Research
                Award Recipient :
                Funded by: Foundation for Urologic Research
                Award Recipient :
                Funded by: Foundation for Urologic Research
                Award Recipient :
                This work was supported by the Foundation of Urologic Research Berlin ( http://stiftung-urologie.de/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and life sciences
                Subject: Genetics
                Subject: Gene expression
                Subject: Gene regulation
                Subject: MicroRNAs
                Subject: Biology and life sciences
                Subject: Biochemistry
                Subject: Nucleic acids
                Subject: RNA
                Subject: Non-coding RNA
                Subject: MicroRNAs
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Metastatic Tumors
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Carcinomas
                Subject: Renal Cell Carcinoma
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Genitourinary Tract Tumors
                Subject: Renal Cell Carcinoma
                Subject: Research and Analysis Methods
                Subject: Bioassays and Physiological Analysis
                Subject: Microarrays
                Subject: Biology and Life Sciences
                Subject: Molecular Biology
                Subject: Molecular Biology Techniques
                Subject: Transfection
                Subject: Research and Analysis Methods
                Subject: Molecular Biology Techniques
                Subject: Transfection
                Subject: Research and Analysis Methods
                Subject: Specimen Preparation and Treatment
                Subject: Staining
                Subject: Cytoplasmic Staining
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Metastasis
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Basic Cancer Research
                Subject: Metastasis
                Subject: Biology and Life Sciences
                Subject: Molecular Biology
                Subject: Molecular Biology Techniques
                Subject: Artificial Gene Amplification and Extension
                Subject: Polymerase Chain Reaction
                Subject: Research and Analysis Methods
                Subject: Molecular Biology Techniques
                Subject: Artificial Gene Amplification and Extension
                Subject: Polymerase Chain Reaction
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting Information files and raw data are found in the database figshare, DOI no. 10.6084/m9.figshare.3123388, respectively.

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                ScienceOpen disciplines: Uncategorized

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