Li Mengjie, Cao Qing, Ding Xuzhong, Liu Anning, Xu Yu, Gu Kang, Peng Yin, Li Peng
Department of General Surgery, Affiliated Hospital and Medical School of Nantong University, Nantong, 226001, China.
Department of Gastrointestinal Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China.
J Mol Histol. 2025 Sep 6;56(5):297. doi: 10.1007/s10735-025-10588-z.
Pseudoautosomal regions (PARs), located at the ends of sex chromosomes, harbor genes that may play a role in tumor pathology by regulating cell proliferation and the immune microenvironment. Gastric cancer (GC) is a prevalent and molecularly heterogeneous malignancy of the digestive system. However, studies on the role of PARs-related genes in GC are limited. This study focuses on the PARs gene CSF2RA and its regulatory role in GC progression through the JAK2/STAT3 signaling pathway. Differentially expressed PARs-related genes associated with GC were identified using multi-omics datasets(including TCGA-STAD and four GEO cohorts). Functional enrichment, immune infiltration, and drug sensitivity analyses, combined with in vitro (using MKN45 and AGS cell lines) and in vivo experiments, were conducted to validate the role of CSF2RA in GC. Additionally, RT-qPCR, Western blot, immunofluorescence, and co-immunoprecipitation assays were performed to investigate the interaction between CSF2RA and JAK2 and their activation of downstream signaling pathways. CSF2RA was found to be highly expressed in GC and associated with poor prognosis. It was significantly enriched in the JAK/STAT signaling pathway and closely related to immune cell infiltration. Furthermore, CSF2RA promoted GC cell proliferation and metastasis by activating the JAK2/STAT3 pathway. The JAK inhibitor Ruxolitinib effectively reversed the tumor-promoting effects of CSF2RA and demonstrated significant inhibitory effects in both in vitro and in vivo experiments. This study is the first to reveal the tumor-promoting mechanism of CSF2RA in GC, demonstrating its role in facilitating tumor progression via the JAK2/STAT3 signaling pathway. The potential therapeutic value of Ruxolitinib was validated in both cell-based and xenograft tumor models. Future research should further explore the upstream regulatory mechanisms of CSF2RA and its dynamic role in the immune microenvironment to advance precision treatment strategies for GC.
假常染色体区域（PARs）位于性染色体末端，含有可能通过调节细胞增殖和免疫微环境在肿瘤病理学中发挥作用的基因。胃癌（GC）是消化系统中一种常见且分子异质性的恶性肿瘤。然而，关于PARs相关基因在GC中的作用的研究有限。本研究聚焦于PARs基因CSF2RA及其通过JAK2/STAT3信号通路在GC进展中的调节作用。使用多组学数据集（包括TCGA - STAD和四个GEO队列）鉴定与GC相关的差异表达的PARs相关基因。进行功能富集、免疫浸润和药物敏感性分析，并结合体外实验（使用MKN45和AGS细胞系）和体内实验，以验证CSF2RA在GC中的作用。此外，进行了RT - qPCR、蛋白质免疫印迹、免疫荧光和免疫共沉淀实验，以研究CSF2RA与JAK2之间的相互作用及其对下游信号通路的激活。发现CSF2RA在GC中高表达且与不良预后相关。它在JAK/STAT信号通路中显著富集，并且与免疫细胞浸润密切相关。此外，CSF2RA通过激活JAK2/STAT3通路促进GC细胞增殖和转移。JAK抑制剂鲁索替尼有效地逆转了CSF2RA的促肿瘤作用，并在体外和体内实验中均显示出显著的抑制作用。本研究首次揭示了CSF2RA在GC中的促肿瘤机制，证明了其通过JAK2/STAT3信号通路促进肿瘤进展的作用。鲁索替尼的潜在治疗价值在基于细胞的模型和异种移植肿瘤模型中均得到验证。未来的研究应进一步探索CSF2RA的上游调节机制及其在免疫微环境中的动态作用，以推进GC的精准治疗策略。
