microRNAs in RCC: Identification and Their Role

A Panel of microRNAs for the Detection and Prognosis of Renal Cell Cancer

There is a critical need for reliable biomarkers for the early detection, prognosis, and therapeutic targeting of renal cell cancer (RCC). MicroRNAs (miRNAs)—short, non-coding RNA molecules—have emerged as promising candidates due to their dual role as upregulated oncogenes (oncomiRs) or downregulated tumor suppressors (tsmiRs) in tumorigenesis. Their unique expression patterns, stability in bodily fluids such as plasma or serum, and tissue specificity make miRNAs ideal candidates as biomarkers for clear cell renal cell carcinoma (ccRCC).

This study aimed to identify key miRNAs differentially expressed in ccRCC tissues and to investigate and validate their clinical relevance in disease progression, relapse, and survival.

Methods

RNA sequencing and miRNA expression profiles were retrieved from the NCBI GEO and TCGA databases using the Illumina HiScanSQ platform. Differential expression analysis was performed using the DESeq2 package. Our dataset included RNA isolated from 26 ccRCC tumor tissue samples and 26 adjacent normal tissues obtained from radical nephrectomy specimens at the Department of Urology, IMS-BHU, between March and December 2023.

Real-time PCR validated selected candidate miRNAs showing significant expression differences between ccRCC and normal tissues, filtered using the Benjamini–Hochberg method over the UALCAN database. Putative target genes of the selected miRNAs were predicted using miRDB and Starbase ENCORI bioinformatics platforms. These were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis using ShinyGO v0.80. Network analysis of miRNAs and their target genes was performed using Cytoscape v3.10.1.

Results

Five miRNAs showed significant differential expression in ccRCC compared with normal tissue on qPCR:

• Upregulated (OncomiRs): miR-21, miR-210

• Downregulated (tsmiRs): miR-29, miR-33, miR-145

These miRNAs collectively influenced signaling pathways such as PI3K/AKT, mTOR, and hypoxia response. Pathway and GO analysis of their predicted target genes revealed enrichment in cancer-related processes including cell cycle regulation, apoptosis, angiogenesis, DNA repair, and cell adhesion (Figures 1 and 2).

ROC analysis demonstrated strong diagnostic accuracy of the miRNA panel [AUC 0.934 (95% CI 0.886–0.982), sensitivity 0.894, specificity 0.872], supporting their potential as reliable biomarkers for early detection and disease monitoring. Survival analysis showed that high expression of miR-21 and miR-210 correlated with shorter overall and progression-free survival, while elevated levels of miR-145, miR-29, and miR-33 were associated with improved outcomes.

The upregulated oncomiRs—particularly miR-21 and miR-210—activate key survival and adaptation pathways, such as HIF-1α and PI3K/AKT, promoting angiogenesis and resistance to apoptosis. Conversely, loss of tumor-suppressive miRNAs like miR-145 removes inhibition of cell proliferation and migration, facilitating rapid tumor growth and metastasis.

Conclusion

Integration of clinical datasets (e.g., TCGA via UALCAN) with patient-derived tissue experiments highlights the translational potential of miRNAs as diagnostic liquid biopsy markers, prognostic tools, and therapeutic targets through RNA modulation.

This study identifies and validates key miRNA markers involved in critical cancer-related pathways, with promising applications in early detection, relapse prediction, survival assessment, and precision therapeutics for RCC.

Dr. Yashaswi Singh, IMS-BHU, Varanasi