miRNAs as potential regulators of mTOR pathway in renal cell carcinoma (original) (raw)
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MicroRNAs: exploring a new dimension in the pathogenesis of kidney cancer
2010
Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. The role of the von-Hippel-Lindeau (VHL) tumour suppressor gene is well established in RCC with a loss of VHL protein leading to accumulated hypoxia-induced factor (HIF) and the subsequent transcriptional activation of multiple downstream targets. Recently, microRNAs (miRNAs) have been shown to be differentially expressed in RCC and their role in RCC pathogenesis is emerging. This month, in BMC Medicine, Gleadle and colleagues show that certain miRNAs are regulated by VHL in either a hypoxia-inducible factor (HIF)-dependent or HIF-independent manner in RCC. They also show that miRNA expression correlates with the survival of RCC patients. In this commentary, we discuss the current understanding of the role of miRNAs in RCC and the different possible scenarios of their involvement in RCC pathogenesis. We also address their clinical significance as tumour markers, together with the potential use of miRNAs as therapeutic targets. Finally, we discuss some of the challenges that face the fast-evolving field of miRNAs, including the identification and validation of miRNA targets and the difficulties associated with establishing a link between miRNA expression and biological effects. A more thorough understanding of the biological nature of miRNAs and careful experimental planning will help us to reveal the complex role that miRNAs play in RCC pathogenesis.
2011
PURPOSE: Renal cell carcinoma is the most common neoplasm of the adult kidney. Currently to our knowledge there are no biomarkers for diagnostic, prognostic or predictive applications for renal cell carcinoma. miRNAs are nonprotein coding RNAs that negatively regulate gene expression and are potential biomarkers for cancer. MATERIALS AND METHODS: We analyzed 70 matched pairs of clear cell renal cell carcinoma and normal kidney tissues from the same patients by microarray analysis and validated our results by quantitative real-time polymerase chain reaction. We also performed extensive bioinformatic analysis to explore the role and regulation of miRNAs in clear cell renal cell carcinoma. RESULTS: We identified 166 miRNAs that were significantly dysregulated in clear cell renal cell carcinoma, including miR-122, miR-155 and miR-210, which had the highest over expression, and miR-200c, miR-335 and miR-218, which were most down-regulated. Analysis of previously reported miRNAs dysregulated in RCC showed overall agreement in the direction of dysregulation. Extensive target prediction analysis revealed that many miRNAs were predicted to target genes involved in renal cell carcinoma pathogenesis. In renal cell carcinoma miRNA dysregulation can be attributed in part to chromosomal aberrations, co-regulation of miRNA clusters and co-expression with host genes. We also performed a preliminary analysis showing that miR-155 expression correlated with clear cell renal cell carcinoma size. This finding must be validated in a larger independent cohort. CONCLUSIONS: Analysis showed that miRNAs are dysregulated in clear cell renal cell carcinoma and may contribute to kidney cancer pathogenesis by targeting more than 1 key molecule. We identified mechanisms that may contribute to miRNA dysregulation in clear cell renal cell carcinoma. Dysregulated miRNAs represent potential biomarkers for kidney cancer.
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2012
Metastasis results in most of the cancer deaths in clear cell renal cell carcinoma (ccRCC). MicroRNAs (miRNAs) regulate many important cell functions and play important roles in tumor development, metastasis and progression. In our previous study, we identified a miRNA signature for metastatic RCC. In this study, we validated the top differentially expressed miRNAs on matched primary and metastatic ccRCC pairs by quantitative polymerase chain reaction. We performed bioinformatics analyses including target prediction and combinatorial analysis of previously reported miRNAs involved in tumour progression and metastasis. We also examined the co-expression of the miRNAs clusters and compared expression of intronic miRNAs and their host genes. We observed significant dysregulation between primary and metastatic tumours from the same patient. This indicates that, at least in part, the metastatic signature develops gradually during tumour progression. We identified metastasis-dysregulated miRNAs that can target a number of genes previously found to be involved in metastasis of kidney cancer as well as other malignancies. In addition, we found a negative correlation of expression of miR-126 and its target vascular endothelial growth factor (VEGF)-A. Cluster analysis showed that members of the same miRNA cluster follow the same expression pattern, suggesting the presence of a locus control regulation. We also observed a positive correlation of expression between intronic miRNAs and their host genes, thus revealing another potential control mechanism for miRNAs. Many of the significantly dysregulated miRNAs in metastatic ccRCC are highly conserved among species. Our analysis suggests that miRNAs are involved in ccRCC metastasis and may represent potential biomarkers.
Mathematical Biology and Bioinformatics
MicroRNAs are non-coding molecules 21–23 nucleotides long that are involved in post-transcriptional regulation of gene expression by mRNA silencing. There is evidence that miRNA activity is associated with various types of human cancer, such as breast cancer, colorectal cancer, ovarian cancer and hepatocellular carcinoma, as well as with clear cell renal cell carcinoma. In 2020, the incidence of kidney cancer worldwide was 319,016. Clear cell renal cell carcinoma is associated with loss or mutation of the VHL gene. The aim of this study was to identify miRNAs that are expressed differently in samples of normal kidney tissue and tissue affected by clear cell renal cell carcinoma. For this study, a public miRNA dataset from ArrayExpress was obtained and post-processed. Mapping, identification of known and new microRNAs, and quantification were performed using the miRDeep2 computer program from the DESeq R/Bioconductor package. We performed target identification and functional load ana...
Oncogenic MicroRNAs Characterization in Clear Cell Renal Cell Carcinoma
International journal of molecular sciences, 2015
A key challenge for the improvement of clear cell renal cell carcinoma (ccRCC) management could derive from a deeper characterization of the biology of these neoplasms that could greatly improve the diagnosis, prognosis and treatment choice. The aim of this study was to identify specific miRNAs that are deregulated in tumor vs. normal kidney tissues and that could impact on the biology of ccRCC. To this end we selected four miRNAs (miR-21-5p, miR-210-3p, miR-185-5p and miR-221-3p) and their expression has been evaluated in a retrospective cohort of formalin-fixed paraffin-embedded (FFPE) tissues from 20 ccRCC patients who underwent surgical nephrectomy resection. miR-21-5p and miR-210-3p resulted the most significantly up-regulated miRNAs in this patient cohort, highlighting these onco-miRNAs as possible relevant players involved in ccRCC tumorigenesis. Thus, this study reports the identification of specific oncogenic miRNAs that are altered in ccRCC tissues and suggests that they m...
Differential expression of microRNA501-5p affects the aggressiveness of clear cell renal carcinoma
FEBS Open Bio, 2014
MicroRNA501-5p mTOR signaling p53 Apoptosis Cell survival a b s t r a c t Renal cell carcinoma is a common neoplasia of the adult kidney that accounts for about 3% of adult malignancies. Clear cell renal carcinoma is the most frequent subtype of kidney cancer and 20-40% of patients develop metastases. The absence of appropriate biomarkers complicates diagnosis and prognosis of this disease. In this regard, small noncoding RNAs (microRNAs), which are mutated in several neoplastic diseases including kidney carcinoma, may be optimal candidates as biomarkers for diagnosis and prognosis of this kind of cancer. Here we show that patients with clear cell kidney carcinoma that express low levels of miR501-5p exhibited a good prognosis compared with patients with unchanged or high levels of this microRNA. Consistently, in kidney carcinoma cells the downregulation of miR501-5p induced an increased caspase-3 activity, p53 expression as well as decreased mTOR activation, leading to stimulation of the apoptotic pathway. Conversely, miR501-5p upregulation enhanced the activity of mTOR and promoted both cell proliferation and survival. These biological processes occurred through p53 inactivation by proteasome degradation in a mechanism involving MDM2-mediated p53 ubiquitination. Our results support a role for miR501-5p in balancing apoptosis and cell survival in clear cell renal carcinoma. In particular, the downregulation of microRNA501-5p promotes a good prognosis, while its upregulation contributes to a poor prognosis, in particular, if associated with p53 and MDM2 overexpression and mTOR activation. Thus, the expression of miR501-5p is a possible biomarker for the prognosis of clear cell renal carcinoma.
MicroRNAs and their target gene networks in renal cell carcinoma
Biochemical and Biophysical Research Communications, 2011
a b s t r a c t MicroRNAs (miRNAs) are non-protein-coding short single stranded RNAs in the size range 19-25 nucleotides that are associated with gene regulation at the transcriptional and translational level. Recent studies have proved that miRNAs play important roles in a large number of biological processes, including cellular differentiation, proliferation, apoptosis, etc. Changes in their expression were found in a variety of human cancers, including renal cell carcinoma pathogenesis. Specific miRNA alterations were associated with key pathogenetic mechanisms of renal cell carcinoma like hypoxia or epithelial-mesenchymal transition. In this review, we summarize the current knowledge of miRNA functions in renal cell carcinoma with an emphasis on miRNAs potential to serve as a powerful biomarker of disease and a novel therapeutic target in oncology.
2011
Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney, accounting for a total of 2-3% of adult neoplasias, and it arises from the renal epithelium. Clear cell renal cell carcinoma (ccRCC) is the most common, invasive and metastatic among RCC subtypes, representing 75-80% of kidney primary malignancies. The von Hippel-Lindau (VHL) gene, which is the main tumor suppressor gene involved in early steps of RCC tumorigenesis, undergoes complete inactivation by mutation, deletion, and promoter methylation in the majority of sporadic ccRCCs and in all inherited forms. Defining the prognosis for RCC cases is important for both decision-making and counseling patients, but sometimes the diagnosis is difficult because tumor subtypes have overlapping histo-pathological features, thus resulting undistinguishable by microscopy investigation. In recent years, in several human cancers, microarray gene expression profiling proved to be a powerful tool to better classify tumor subtypes and to identify novel molecular biomarkers potentially useful for clinical applications. In fact, tumor transcriptomic profiling may identify patterns of genes that are functionally related to patients" prognosis, response to therapy and overall survival. Recent evidences have shown that microRNA (miRNA) molecules are involved in tumorigenesis, indicating that miRNAs might function as both tumor suppressors and oncogenes, and their role in RCC pathogenesis is now emerging. miRNAs are small single-stranded non-protein-coding RNA molecules, that function as negative post-transcriptional gene regulators in animals, plants and viruses, and are involved in many biological processes, also including haematopoietic cell differentiation, apoptosis, cell proliferation and organ development. miRNA and gene expression patterns are closely related, since they cooperatively work to create gene regulatory networks. Therefore, integrative genomics approach might be a useful tool to elucidate the complex relationships underlying these networks. The aim of my PhD fellowship work was to reconstruct miRNA-gene post-transcriptional regulatory networks involved in RCC biology, using miRNA and gene expression profiles of three RCC cell lines compared to a normal one, obtained by Affymetrix high-density microarray technology. We calculated differentially expressed genes and miRNAs, and, by functional enrichment analysis, we identified genes and miRNAs that were already known to be associated with RCC and involved in relevant pathways for this pathology, such as hypoxia, p53 signaling, focal adhesion, angiogenesis and mTOR signaling. Through integrated analysis of miRNA-gene expression profiles, we reconstructed potentially active regulatory networks involving miRNAs and their predicted target genes. We validated some miRNA-gene pairs by quantitative PCR, thus confirming their anti-correlated expression levels. Our results demonstrated that RCC cell lines can be an useful in vitro model for RCC pathology, since they showed gene and miRNA expression profiles similar to renal tumoral tissues, as obtained by comparing our results with published data. The analysis of the correlations between gene and miRNA expression profiles using a genome-wide integrative approach could help the identification of both post-transcriptional regulatory networks and novel candidate markers functionally relevant for RCC pathology. However, further investigations are necessary to elucidate the actual role of miRNA-gene networks in the context of RCC progression and outcome. VIII