Abstract
MicroRNAs (miRNA) are non-coding RNAs, approximately 22 nucleotides in length, which function as post-transcriptional regulators. A large body of evidence indicates that miRNAs regulate the expression of cancer-related genes involved in proliferation, migration, invasion, and metastasis. The aim of this study was to identify novel cancer networks in renal cell carcinoma (RCC) based on miRNA expression signatures obtained from RCC clinical specimens. Expression signatures revealed that 103 miRNAs were significantly downregulated (more than 0.5-fold change) in RCC specimens. Functional screening (cell proliferation assays) was performed to identify tumor suppressive activities of 20 downregulated miRNAs. Restoration of mature miRNAs in cancer cells showed that 14 miRNAs (miR-1285, miR-206, miR-1, miR-135a, miR-429, miR-200c, miR-1291, miR-133b, miR-508-3p, miR-360-3p, miR-509-5p, miR-218, miR-335, miR-1255b and miR-1285) markedly inhibited cancer cell proliferation, suggesting that these miRNAs were candidate tumor suppressive miRNAs in RCC. We focused on miR-1285 because it significantly inhibited cancer cell proliferation, invasion, and migration following its transfection. We addressed miR-1285-regulated cancer networks by using genome-wide gene expression analysis and bioinformatics. The data showed that transglutaminase 2 (TGM2) was directly regulated by miR-1285. Silencing of the target gene demonstrated significant inhibition of cell proliferation and invasion in the RCC cells. Furthermore, immunohistochemistry showed that TGM2 expression levels in RCC specimens were significantly higher than those in normal renal tissues. Downregulation of tumor suppressive miR-1285, which targets oncogenic genes including TGM2, might contribute to RCC development. Thus, miR-1285 modulates a novel molecular target and provides new insights into potential mechanisms of RCC oncogenesis.
Highlights
Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney, and clear cell renal cell carcinoma (RCC) represents the most common renal cancer histology [1]
We evaluated mature miRNA expression levels of clinical RCC specimens by miRNA expression signature analysis
Expression signatures revealed that 103 miRNAs were downregulated (< 0.5-fold change) in RCC specimens (Supplementary Table 1)
Summary
Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney, and clear cell RCC represents the most common renal cancer histology [1]. New therapeutic drugs have been developed for treatment of metastatic RCC. It is crucial to find novel molecular mechanisms based on recent genome-wide studies including non-coding RNAs (ncRNA) in RCC oncogenesis and metastasis. RNA can be divided into two categories, protein coding RNA and ncRNA. It is important to examine the functions of ncRNAs and their association with human disease, including cancer. MicroRNAs (miRNAs) are endogenous small ncRNA molecules (~19 - 22 bases) that regulate protein coding gene expression by repressing translation or cleaving RNA transcripts in a sequencespecific manner [4]. A growing body of evidence suggests that miRNAs are aberrantly expressed in many human cancers, and that they play significant roles in their initiation, development, and metastasis [5]. Some highly expressed miRNAs could function as oncogenes by repressing tumor suppressors, whereas low level miRNAs could function as tumor suppressors by negatively regulating oncogenes [6]
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