CRHBP-UCN2 Axis Critically Regulates Kidney Cancer Prognosis, Identifies CRHBP as Potential Anticancer Peptide Target
Background
Kidney renal clear cell carcinoma (KIRC), the most common subtype of renal cell carcinoma (RCC), carries a poor clinical prognosis, particularly due to its association with genomic aberrations and immune microenvironment disorders. Current standard-of-care treatments, including surgery, targeted therapies, and immunotherapies, often fall short for advanced and metastatic cases. There is a critical need to identify novel prognostic biomarkers and effective therapeutic targets to improve patient outcomes and overcome treatment resistance in KIRC.
Study Design
Researchers conducted a multi-omics integrative analysis of KIRC using transcriptome, methylation, copy number variation (CNV), and immune infiltration data from public databases. This in silico analysis was further validated using single-cell RNA sequencing (scRNA-seq), two-sample Mendelian randomization (TSMR), in silico gene knockout experiments, and quantitative PCR (qPCR). The qPCR validation specifically assessed CRHBP expression in human KIRC tissues and UCN2 expression in mouse KIRC tissues to provide preliminary in vivo and ex vivo corroboration.
Results
Results demonstrated that CRHBP was a core downregulated prognostic biomarker in KIRC, exhibiting stage-dependent low expression and a favorable survival predictive value. Patients with higher CRHBP expression showed significantly better overall survival, with an OS HR = 0.42 (95%CI: 0.395-0.45, P<0.05). ScRNA-seq further revealed a compartmentalized CRHBP expression pattern and its differential regulation by immune checkpoint blockade (ICB) treatment and gender. TSMR confirmed a causal risk effect of testicular-derived UCN2 on KIRC, where UCN2 negatively correlated with tumor angiogenesis and hypoxia. Molecular docking screened dabrafenib as a promising candidate drug targeting the CRHBP/UCN2 axis, showing strong binding affinities of -11.55 kcal/mol for CRHBP and -17.23 kcal/mol for UCN2. > In silico knockout of CRHBP significantly altered SRGN/TYROBP expression and inhibited cytokine production, highlighting its role in immune modulation. QPCR verified decreased CRHBP expression in human KIRC tissues and elevated UCN2 expression in mouse KIRC tissues, supporting the in silico findings.
Key Findings
- CRHBP is a core downregulated prognostic biomarker in KIRC, with an
OS HR = 0.42(P<0.05). ScRNA-seqrevealed compartmentalized CRHBP expression differentially regulated by ICB treatment and gender.- Testicular-derived UCN2 causally increases KIRC risk and negatively correlates with tumor angiogenesis and hypoxia.
- Molecular docking identified dabrafenib as a promising candidate targeting CRHBP/UCN2 (binding affinity:
-11.55/-17.23 kcal/mol). In silicoCRHBP knockout alteredSRGN/TYROBPexpression and inhibited cytokine production.
Why It Matters
This study significantly advances our understanding of KIRC progression by identifying the CRHBP-UCN2 axis as a critical regulator of prognosis and immune microenvironment remodeling. CRHBP emerges as a reliable prognostic biomarker and, importantly, a potential anticancer peptide target, opening new avenues for therapeutic intervention. The identification of dabrafenib as a promising candidate drug targeting this axis provides a starting point for drug repurposing or development. This research suggests that future clinical strategies for KIRC could involve modulating the CRHBP-UCN2 pathway, potentially through peptide-based therapies or small molecule inhibitors, to improve patient outcomes and enhance immunotherapy responses. Further research is needed to translate these in silico and preliminary in vivo findings into human clinical protocols.
kirc
renal-cell-carcinoma
multi-omics
biomarker
crhbp
ucn2