Chinese PLA Medical School, Beijing, PR China.
Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, PR China.
J Pathol. 2024 Oct;264(2):228-240. doi: 10.1002/path.6340. Epub 2024 Aug 2.
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.
Xp11.2 易位肾细胞癌（tRCC）是一种罕见且高度恶性的肾癌，缺乏有效的诊断指标和治疗靶点。通过对公共数据库和我们队列的分析，我们发现 NMRK2 是一种潜在的诊断标志物，可用于区分 Xp11.2 tRCC 与肾透明细胞癌（KIRC）和肾乳头状细胞癌（KIRP），因为它在 Xp11.2 tRCC 组织中特异性上调。从机制上讲，我们发现 TFE3 融合蛋白与 NMRK2 基因的启动子结合，导致其上调。重要的是，我们建立了基于 RNA 和蛋白质的诊断方法，根据 NMRK2 表达水平识别 Xp11.2 tRCC，我们方法的诊断性能可与双颜色分离荧光原位杂交检测相媲美。此外，我们成功地使用我们的诊断方法鉴定了手术切除后的新鲜 Xp11.2 tRCC 组织，并建立了一个永生化的 Xp11.2 tRCC 细胞系，用于进一步研究。功能研究表明，NMRK2 通过上调 NAD/NADH 比值促进 Xp11.2 tRCC 的进展，补充 β-烟酰胺单核苷酸（NMN）或烟酰胺核糖氯化物（NR）可有效挽救 Xp11.2 tRCC 中 NMRK2 敲低诱导的表型。综上所述，这些数据提供了一种新的诊断指标，能够准确地区分 Xp11.2 tRCC，并强调了开发新型靶向治疗的可能性。
