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Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
Exploring the miRNA-mRNA regulatory network in clear cell renal cell carcinomas by next-generation sequencing
Sören Müller1, Katharina Nowak2
1Plant Molecular Biology, Molecular BioSciences, Goethe University, Marie-Curie-Street 9, 60439 Frankfurt, Germany ; GenXpro GmbH, Frankfurt Biotechnology Innovation Center, Altenhöferallee 3, 60438 Frankfurt, Germany.
Abstract:
Altered microRNA (miRNA) expression is a hallmark of many cancer types. The combined analysis of miRNA and messenger RNA (mRNA) expression profiles is crucial to identifying links between deregulated miRNAs and oncogenic pathways. Therefore, we investigated the small non-coding (snc) transcriptomes of nine clear cell renal cell carcinomas (ccRCCs) and adjacent normal tissues for alterations in miRNA expression using a publicly available small RNA-Sequencing (sRNA-Seq) raw-dataset. We constructed a network of deregulated miRNAs and a set of differentially expressed genes publicly available from an independent study to in silico determine miRNAs that contribute to clear cell renal cell carcinogenesis. From a total of 1,672 sncRNAs, 61 were differentially expressed across all ccRCC tissue samples. Several with known implications in ccRCC development, like the upregulated miR-21-5p, miR-142-5p, as well as the downregulated miR-106a-5p, miR-135a-5p, or miR-206. Additionally, novel promising candidates like miR-3065, which i.a. targets NRP2 and FLT1, were detected in this study. Interaction network analysis revealed pivotal roles for miR-106a-5p, whose loss might contribute to the upregulation of 49 target mRNAs, miR-135a-5p (32 targets), miR-206 (28 targets), miR-363-3p (22 targets), and miR-216b (13 targets). Among these targets are the angiogenesis, metastasis, and motility promoting oncogenes c-MET, VEGFA, NRP2, and FLT1, the latter two coding for VEGFA receptors.
Insights
This study analyzed microRNA (miRNA) expression in clear cell renal cell carcinoma (ccRCC), identifying key miRNAs like miR-106a-5p and miR-135a-5p that may drive cancer progression by targeting oncogenes involved in angiogenesis and metastasis.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Altered microRNA (miRNA) expression is a common feature in various cancers, including clear cell renal cell carcinoma (ccRCC).
- Analyzing both miRNA and messenger RNA (mRNA) expression is vital for understanding how deregulated miRNAs influence oncogenic pathways.
Purpose of the Study:
- To investigate alterations in miRNA expression within ccRCC tumors compared to adjacent normal tissues.
- To identify specific miRNAs and their mRNA targets implicated in ccRCC development and progression.
Main Methods:
- Utilized publicly available small RNA-Sequencing (sRNA-Seq) data from nine ccRCC and normal tissue pairs.
- Performed differential expression analysis to identify altered small non-coding RNAs (sncRNAs).
- Constructed interaction networks between differentially expressed miRNAs and target genes from an independent dataset to infer functional roles.
Main Results:
- Identified 61 differentially expressed sncRNAs among 1,672 analyzed, with several known ccRCC-associated miRNAs (e.g., upregulated miR-21-5p, downregulated miR-106a-5p).
- Discovered novel candidate miRNAs, such as miR-3065, targeting key genes like NRP2 and FLT1.
- Network analysis highlighted miR-106a-5p, miR-135a-5p, and miR-206 as pivotal, with their dysregulation potentially affecting numerous oncogenic targets, including VEGFA, c-MET, NRP2, and FLT1.
Conclusions:
- The study identified specific miRNA expression profiles associated with ccRCC.
- Dysregulated miRNAs, particularly miR-106a-5p and miR-135a-5p, play significant roles in ccRCC pathogenesis by influencing critical oncogenes involved in angiogenesis, metastasis, and cell motility.
- These findings suggest potential diagnostic and therapeutic targets for ccRCC.
