<b>The role of the </b><b>LncRNA </b><b>XIST/miR-15a-5p/ MN1</b><b>signaling </b><b>axis in gender disparities in bladder cancer prognosis</b>

Through comprehensive analysis of the GSE13507 and The Cancer Genome Atlas (TCGA) cohorts, we identified the X chromosome gene long non-coding RNA (LncRNA) X-inactive specific transcript (XIST) as a critical factor in BC sex disparity. Increased XIST mRNA levels were significantly associated with dismal overall survival in female BC patients. Functional assays demonstrated that XIST promotes tumor cell proliferation, migration, and invasion of BC cells in vitro and in vivo. Further investigation revealed that XIST exerts these activities via the miR-15a-5p/meningioma 1 (MN1) signaling axis, which in turn upregulates frizzled class receptor 2 (FZD2) expression. Notably, FZD2 is an important receptor in the Wnt/β-catenin signaling pathway, overexpressed in BC and various malignant tumors. BC patient specimen analysis revealed that XIST and MN1 were significantly upregulated in BC tissues, with a higher fold increase in females. Conversely, miR-15a-5p expression was downregulated in BC tissues, with a greater fold decrease observed in females.<b>Conclusions</b><b>：</b>The XIST/miR-15a-5p/MN1/FZD2 signaling axis emerges as a key contributor to gender disparities in bladder cancer prognosis. XIST represents a potential therapeutic target, particularly for female patients.

通过对GSE13507数据集与癌症基因组图谱（The Cancer Genome Atlas, TCGA）队列进行综合分析，我们鉴定出X染色体上的长链非编码RNA（long non-coding RNA, LncRNA）基因X染色体失活特异性转录本（X-inactive specific transcript, XIST）是膀胱癌（bladder cancer, BC）性别差异的关键调控因子。XIST信使RNA（messenger RNA, mRNA）水平升高与女性膀胱癌患者不良的总体生存率显著相关。功能实验证实，XIST可在体内外促进膀胱癌细胞的增殖、迁移与侵袭能力。进一步研究揭示，XIST通过miR-15a-5p/脑膜瘤1（meningioma 1, MN1）信号轴发挥上述调控作用，进而上调卷曲蛋白家族受体2（frizzled class receptor 2, FZD2）的表达。值得注意的是，FZD2是Wnt/β-连环蛋白信号通路中的重要受体，在膀胱癌及多种恶性肿瘤中呈高表达状态。对膀胱癌患者标本的分析显示，XIST与MN1在膀胱癌组织中显著上调，且女性患者的上调倍数更高。与之相反，miR-15a-5p在膀胱癌组织中表达下调，女性患者的下调幅度更为显著。<b>结论</b>：XIST/miR-15a-5p/MN1/FZD2信号轴是导致膀胱癌预后性别差异的关键因素。XIST有望成为潜在的治疗靶点，尤其适用于女性患者。