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Identification of dysregulated serum miR-508-3p and miR-885-5p as potential diagnostic biomarkers of clear cell renal carcinoma.

ABSTRACT: Clear cell renal cell carcinoma (ccRCC), the most common subtype, accounts for approximately 80% of all RCC cases. ccRCC patients typically present with an advanced stage at the time of diagnosis resulting in a poor patient prognosis. The present study aimed to identify novel potential microRNAs (miRNAs or miRs) in peripheral blood as biomarkers for the detection of ccRCC. Candidate miRNAs were selected through integrated analysis of the Gene Expression Omnibus (GEO) database, The Cancer Genome Atlas (TCGA) database, and from clinical samples. The expression levels of miRNAs were quantified using reverse transcription?quantitative PCR. Receiver operating characteristic (ROC) curve analysis was used to explore the diagnostic values of the miRNAs. Bioinformatic analysis of candidate miRNAs was conducted by using the STRING database. After an integrated analysis of the GEO and TCGA databases, four miRNAs were found to be consistently dysregulated in ccRCC tissues. Then, their expression levels in serum and diagnostic utilities were further explored. We discovered that serum miR?508?3p and miR?885?5p were significantly dysregulated in ccRCC patients with marked diagnostic values. The area under the ROC curve (AUC) of serum miR?508?3p and miR?885?5p was 0.80 (95% CI, 0.73?0.87) and 0.87 (95% CI, 0.79?0.95), respectively. Functional enrichment analysis revealed that both miR?508?3p and miR?885?5p were closely associated with cellular metabolic processes. In conclusion, serum miR?508?3p and miR?885?5p are novel potential biomarkers for the diagnosis of ccRCC.

SUBMITTER: Liu S

PROVIDER: S-EPMC6854552 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Identification of dysregulated serum miR-508-3p and miR-885-5p as potential diagnostic biomarkers of clear cell renal carcinoma.

Liu Siming S Deng Xiaojun X Zhang Jiong J

Molecular medicine reports 20191022 6

Clear cell renal cell carcinoma (ccRCC), the most common subtype, accounts for approximately 80% of all RCC cases. ccRCC patients typically present with an advanced stage at the time of diagnosis resulting in a poor patient prognosis. The present study aimed to identify novel potential microRNAs (miRNAs or miRs) in peripheral blood as biomarkers for the detection of ccRCC. Candidate miRNAs were selected through integrated analysis of the Gene Expression Omnibus (GEO) database, The Cancer Genome ...[more]

PMID: 31661117

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Project description:IntroductionAccumulating evidence has demonstrated that circular RNAs (circRNAs) play a key role in the tumorigenesis of various types of cancers, including clear cell renal cell carcinoma (ccRCC).Materials and methodsReverse transcription-quantitative polymerase chain reaction was used to detect the expression of circRNA homeodomain interacting protein kinase 3 (circHIPK3) and microRNAs (miRNAs), including miR-508-3p. The clinical measurement of circHIPK3 was evaluated by Kaplan-Meier survival analysis and receiver operating characteristic analysis. Cell Counting Kit-8 and Transwell chamber assays were performed to determine the changes in the proliferative and metastatic ability of A498 and 786-O cells. C-X-C motif chemokine ligand 13 (CXCL13) protein expression was detected by Western blot analysis. The targeted binding effect between miR-508-3p and circHIPK3 or CXCL13 was confirmed by constructed luciferase and RNA immunoprecipitation (RIP) assays, respectively. Fluorescence in situ hybridization (FISH) assay was used to measure the subcellular localization of circHIPK3 and miR-508-3p.ResultsIt was found that circHIPK3 was markedly upregulated in ccRCC tissue and cell lines, and circHIPK3-upregulation was closely correlated with poor clinicopathological features in patients with ccRCC. It was found that both miR-508-3p and circHIPK3 were localized in the cytoplasm of ccRCC cells. The up- and downregulation of circHIPK3 positively regulated ccRCC cell proliferation and metastasis, and this regulatory effect was reversed by miR-508-3p. Through luciferase and RIP assays, it was confirmed that circHIPK3 could interacted with miR-508-3p. Furthermore, it was revealed that CXCL13, which was negatively correlated with miR-508-3p, was upregulated in ccRCC. It was also shown that CXCL13 was a downstream target of miR-508-3p. miR-508-3p suppressed ccRCC cell proliferation and metastasis by targeting CXCL13. Lastly, it was demonstrated that circHIPK3 promoted CXCL13 to facilitate ccRCC cell proliferation and metastasis by decoying miR-508-3p.ConclusionIn brief, the results of the present study showed that circHIPK3 promoted ccRCC cell proliferation and metastasis by altering miR-5083p/CXCL13 signaling. The present findings might provide a novel target for the molecular treatment of ccRCC.

Project description:BackgroundDue 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.MethodsThe 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.ResultsIn 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.ConclusionThese 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.

Dataset Information

Identification of dysregulated serum miR-508-3p and miR-885-5p as potential diagnostic biomarkers of clear cell renal carcinoma.

Publications

Identification of dysregulated serum miR-508-3p and miR-885-5p as potential diagnostic biomarkers of clear cell renal carcinoma.

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