Multi-omics analysis of kidney renal cell carcinoma in silico with preliminary in vivo validation.

BACKGROUND

Kidney renal clear cell carcinoma (KIRC) has a poor clinical prognosis, and its tumor progression and immunotherapy response are closely associated with genomic aberrations and immune microenvironment disorders. This study aimed to identify key prognostic biomarkers and potential therapeutic targets for KIRC via multi-omics integrative analysis and preliminary experimental validation.

METHODS

Multi-omics data including transcriptome, methylation, copy number variation (CNV), and immune infiltration data of KIRC were integrated from public databases, and further validated by single-cell RNA sequencing (scRNA-seq), two-sample Mendelian randomization (TSMR), in silico gene knockout, and quantitative PCR (qPCR).

RESULTS

Results demonstrated that CRHBP was a core downregulated prognostic biomarker in KIRC, with stage-dependent low expression and favorable survival predictive value (OS HR = 0.42, 95%CI: 0.395-0.45, P<0.05). ScRNA-seq revealed a compartmentalized CRHBP expression pattern and its differential regulation by immune checkpoint blockade (ICB) treatment and gender. TSMR confirmed the causal risk effect of testicular-derived UCN2 on KIRC, and UCN2 negatively correlated with tumor angiogenesis and hypoxia. Molecular docking screened dabrafenib as a promising candidate drug targeting CRHBP/UCN2 (binding affinity: -11.55/-17.23 kcal/mol). In silico knockout of CRHBP altered SRGN/TYROBP expression and inhibited cytokine production. QPCR verified decreased CRHBP expression in human KIRC tissues and elevated UCN2 expression in mouse KIRC tissues.

CONCLUSIONS

The CRHBP-UCN2 axis critically regulates KIRC prognosis and immune microenvironment remodeling. CRHBP serves as a reliable prognostic biomarker and a potential anticancer peptide target, while dabrafenib is a promising therapeutic agent for KIRC.