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MicroRNA-194 is a Marker for Good Prognosis in Clear Cell Renal Cell Carcinoma.

ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is the most prevalent adult kidney cancer. Prognostic markers are needed to guide patient management toward aggressive versus more conservative approaches, especially for small tumors ?4 cm. miR-194 was reported to be downregulated in several cancers and is involved in epithelial to mesenchymal transition. We evaluated miR-194 as a prognostic marker in ccRCC. In a cohort of 234 patients with primary ccRCC, we correlated miR-194 expression level with multiple clinicopathological features including disease-free and overall survival, tumor size, clinical stage, and histological grade. Our results shows a stepwise decrease in miR-194 expression from normal kidney to primary ccRCC (P = 0.0032) and a subsequent decrease from primary to metastatic lesions. Additionally, patients with higher miR-194 expression has significantly longer disease-free survival (P = 0.041) and overall survival (P = 0.031) compared to those with lower expression. In multivariate analysis, miR-194-positive tumors retain significance in disease-free survival and overall survival, suggesting miR-194 is an independent marker for good prognosis in ccRCC. Moreover, miR-194 is a marker for good prognosis for patients with small renal masses (P = 0.014). These findings were validated on an independent data set from The Cancer Genome Atlas. We also compared miR-194 expression between RCC subtypes. ccRCC had the highest levels, whereas chromophobe RCC and oncocytoma had comparable lower levels. Target prediction coupled with pathway analysis show that miR-194 is predicted to target key molecules and pathways involved in RCC progression. miR-194 represents a prognostic biomarker in ccRCC.

SUBMITTER: Nofech-Mozes R

PROVIDER: S-EPMC4831284 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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MicroRNA-194 is a Marker for Good Prognosis in Clear Cell Renal Cell Carcinoma.

Nofech-Mozes Roy R Khella Heba W Z HW Scorilas Andreas A Youssef Leza L Krylov Sergey N SN Lianidou Evi E Sidiropoulos Konstantinos G KG Gabril Manal M Evans Andrew A Yousef George M GM

Cancer medicine 20160210 4

Clear cell renal cell carcinoma (ccRCC) is the most prevalent adult kidney cancer. Prognostic markers are needed to guide patient management toward aggressive versus more conservative approaches, especially for small tumors ≤4 cm. miR-194 was reported to be downregulated in several cancers and is involved in epithelial to mesenchymal transition. We evaluated miR-194 as a prognostic marker in ccRCC. In a cohort of 234 patients with primary ccRCC, we correlated miR-194 expression level with multip ...[more]

PMID: 26860079

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Project description:Numerous studies have shown that microRNA (miRNA) serves as key regulatory factors in the origin and development of cancers. However, the biological mechanisms of miRNAs in kidney renal clear cell carcinoma (KIRC) are still unknown. It is necessary to construct an effective miRNA-clinical model to predict the prognosis of KIRC. In this study, 94 differentially expressed miRNAs were found between para-tumor and tumor tissues based on the Cancer Genome Atlas (TCGA) database. Seven miRNAs (hsa-miR-21-5p, hsa-miR-3613-5p, hsa-miR-144-5p, hsa-miR-376a-5p, hsa-miR-5588-3p, hsa-miR-1269a, and hsa-miR-137-3p) were selected as prognostic indicators. According to their cox coefficient, a risk score formula was constructed. Patients with risk scores were divided into high- and low-risk groups based on the median score. Kaplan-Meier curves analysis showed that the low-risk group had a better survival probability compared to the high-risk group. The area under the ROC curve (AUC) value of the miRNA model was 0.744. In comparison with clinical features, the miRNA model risk score was considered as an independent prognosis factor in multivariate Cox regression analysis. In addition, we built a nomogram including age, metastasis, and miRNA prognostic model based on the results of multivariate Cox regression analysis. The decision curve analysis (DCA) revealed the clinical net benefit of the prognostic model. Gene set enrichment analysis (GSEA) results suggested that several important pathways may be the potential pathways for KIRC. The results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis for the target genes of 7 miRNAs revealed that miRNAs may participate in KIRC progression via many specific pathways. Additionally, the levels of seven prognostic miRNAs showed a significant difference between KIRC tissues and adjacent non-tumorous tissues. In conclusion, the miRNA-clinical model provides an effective and accurate way to predict the prognosis of KIRC.

Project description:BackgroundCathepsin Z (CTSZ) is a cathepsin family member that plays a dual role in the adhesion and migration of immune and tumor cells.MethodsThe expression pattern of CTSZ in clear cell renal cell carcinoma (ccRCC) was observed by immunohistochemistry and validated by using double-labeling immunofluorescence. Publicly available single-cell sequencing data was used to further define the cell type-specific CTSZ expression in ccRCC. Methylation modification, immune infiltration, and tumor-related signaling enrichment analyses involving CTSZ were performed using multi-omics data. Data from two independent cohorts of anti-programmed death-1 (PD-1) therapeutic clinical trials were used to investigate correlations between CTSZ levels and treatment responses.ResultsCTSZ was upregulated in ccRCC tissues compared with adjacent normal tissues at the RNA but not in ccRCC cells. Immunohistochemistry indicated that CTSZ was expressed in tumors infiltrated with lymphocytes. Double immunofluorescence demonstrated that CTSZ was co-expressed with CD68 but not CD8. Single-cell transcriptome data showed macrophage-specific expression of CTSZ in ccRCC. High CTSZ expression was significantly correlated with the enrichment of interferon-γ, epithelial-to-mesenchymal transition, cell cycle, apoptosis pathways, and B cell, macrophage, neutrophil, and dendritic cell infiltrations, as well as the expression of immune checkpoints CTLA4, LAG3, HAVCR2, PDCD1LG2, PDCD1, TIGIT, and SIGLEC15. Hypomethylation modification of cg02744249, cg02744249, and cg22145559 were negatively correlated with CTSZ expression, suggesting an epigenetic mechanism for the regulation of CTSZ expression. Clinically, CTSZ levels were associated with the prognosis of patients with ccRCC (hazard ratio=1.5, P=0.007). Notably, patients with higher CTSZ expression had a worse prognosis with anti-PD-1 monotherapy (hazard ratio=1.51, P=0.039).ConclusionMacrophage-specific CTSZ was associated with activation of epithelial-to-mesenchymal transition, cell cycle signatures, and a higher infiltration level of B cells, macrophages, neutrophils, and dendritic cells in the tumor microenvironment. High expression of CTSZ could be considered as a prognostic and treatment response biomarker for patients with ccRCC receiving anti-PD-1 immunotherapy.

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MicroRNA-194 is a Marker for Good Prognosis in Clear Cell Renal Cell Carcinoma.

Publications

MicroRNA-194 is a Marker for Good Prognosis in Clear Cell Renal Cell Carcinoma.

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