NMRK2 is an efficient diagnostic indicator for Xp11.2 translocation renal cell carcinoma
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Huayi Feng1,2, Shouqing Cao3, Shihui Fu4,5
1Chinese PLA Medical School, Beijing, PR China.
Abstract:
Xp11.2 translocation renal cell carcinomas (tRCC) are a rare and highly malignant type of renal cancer, lacking efficient diagnostic indicators and therapeutic targets. Through the analysis of public databases and our cohort, we identified NMRK2 as a potential diagnostic marker for distinguishing Xp11.2 tRCC from kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP) due to its specific upregulation in Xp11.2 tRCC tissues. Mechanistically, we discovered that TFE3 fusion protein binds to the promoter of the NMRK2 gene, leading to its upregulation. Importantly, we established RNA- and protein-based diagnostic methods for identifying Xp11.2 tRCC based on NMRK2 expression levels, and the diagnostic performance of our methods was comparable to a dual-color break-apart fluorescence in situ hybridization assay. Moreover, we successfully identified fresh Xp11.2 tRCC tissues after surgical excision using our diagnostic methods and established an immortalized Xp11.2 tRCC cell line for further research purposes. Functional studies revealed that NMRK2 promotes the progression of Xp11.2 tRCC by upregulating the NAD+/NADH ratio, and supplementation with β-nicotinamide mononucleotide (NMN) or nicotinamide riboside chloride (NR), effectively rescued the phenotypes induced by the knockdown of NMRK2 in Xp11.2 tRCC. Taken together, these data introduce a new diagnostic indicator capable of accurately distinguishing Xp11.2 tRCC and highlight the possibility of developing novel targeted therapeutics. © 2024 The Pathological Society of Great Britain and Ireland.
Insights
Researchers identified NMRK2 as a novel biomarker for Xp11.2 translocation renal cell carcinoma (tRCC), enabling accurate diagnosis. This discovery also opens avenues for new targeted therapies for this rare kidney cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Xp11.2 translocation renal cell carcinoma (tRCC) is a rare, aggressive kidney cancer with limited diagnostic markers and treatments.
- Existing diagnostic methods for tRCC can be complex and time-consuming.
Purpose of the Study:
- To identify a novel diagnostic biomarker for Xp11.2 tRCC.
- To elucidate the mechanism of NMRK2 upregulation in Xp11.2 tRCC.
- To explore NMRK2 as a therapeutic target for Xp11.2 tRCC.
Main Methods:
- Analysis of public databases and patient cohorts to identify differentially expressed genes.
- RNA and protein-based assays for NMRK2 expression.
- Fluorescence in situ hybridization (FISH) for comparison.
- Functional studies involving gene knockdown and metabolite supplementation (NMN, NR).
Main Results:
- NMRK2 was found to be specifically upregulated in Xp11.2 tRCC tissues compared to other kidney cancer subtypes.
- TFE3 fusion protein directly binds to the NMRK2 promoter, driving its overexpression.
- NMRK2-based diagnostic methods demonstrated high accuracy, comparable to FISH assays.
- NMRK2 promotes tRCC progression by increasing the NAD+/NADH ratio; NMN and NR supplementation rescued NMRK2 knockdown phenotypes.
Conclusions:
- NMRK2 serves as a reliable diagnostic marker for distinguishing Xp11.2 tRCC.
- Targeting NMRK2 or modulating NAD+ metabolism presents a potential therapeutic strategy for Xp11.2 tRCC.
