Synaptopodin 2 (SYNPO2) plays a pivotal role in regulating tumor growth, development and progression in bladder urothelial Carcinoma (BLCA). However, the precise biological functions and mechanisms of SYNPO2 in BLCA remain unclear. Based on TCGA database‑derived BLCA RNA sequencing data, survival analysis and prognosis analysis indicate that elevated SYNPO2 expression was associated with poor survival outcomes. Notably, exogenous SYNPO2 expression significantly promoted tumor invasion and migration by upregulating vimentin expression in BLCA cell lines. Enrichment analysis revealed the involvement of SYNPO2 in humoral immune responses and the PI3K/AKT signaling pathway. Moreover, increased SYNPO2 levels increased the sensitivity of BLCA to PI3K/AKT pathway‑targeted drugs while being resistant to conventional chemotherapy. In in vivo BLCA mouse models, SYNPO2 overexpression increased pulmonary metastasis of 5637 cells. High SYNPO2 expression led to increased infiltration of innate immune cells, particularly mast cells, in both nude mouse model and clinical BLCA samples. Furthermore, tumor immune dysfunction and exclusion score showed that patients with BLCA patients and high SYNPO2 expression exhibited worse clinical outcomes when treated with immune checkpoint inhibitors. Notably, in the IMvigor 210 cohort, SYNPO2 expression was significantly associated with the population of resting mast cells in BLCA tissue following PD1/PDL1 targeted therapy. In conclusion, SYNPO2 may be a promising prognostic factor in BLCA by modulating mast cell infiltration and exacerbating resistance to immune therapy and conventional chemotherapy.

中文翻译：

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SYNPO2 通过上调静息肥大细胞的浸润并增加对免疫治疗的抵抗力来促进 BLCA 的发展。

突触蛋白 2 (SYNPO2) 在调节膀胱尿路上皮癌 (BLCA) 的肿瘤生长、发展和进展中发挥着关键作用。然而，SYNPO2在BLCA中的精确生物学功能和机制仍不清楚。根据 TCGA 数据库衍生的 BLCA RNA 测序数据，生存分析和预后分析表明 SYNPO2 表达升高与不良生存结果相关。值得注意的是，外源SYNPO2表达通过上调BLCA细胞系中波形蛋白的表达来显着促进肿瘤侵袭和迁移。富集分析揭示了 SYNPO2 参与体液免疫反应和 PI3K/AKT 信号通路。此外，SYNPO2 水平的升高增加了 BLCA 对 PI3K/AKT 通路靶向药物的敏感性，同时对传统化疗具有耐药性。在体内 BLCA 小鼠模型中，SYNPO2 过度表达增加了 5637 细胞的肺转移。在裸鼠模型和临床 BLCA 样本中，SYNPO2 高表达导致先天免疫细胞（尤其是肥大细胞）的浸润增加。此外，肿瘤免疫功能障碍和排除评分显示，BLCA 患者和 SYNPO2 高表达的患者在接受免疫检查点抑制剂治疗时表现出更差的临床结果。值得注意的是，在 IMvigor 210 队列中，SYNPO2 表达与 PD1/PDL1 靶向治疗后 BLCA 组织中静息肥大细胞群显着相关。总之，SYNPO2 通过调节肥大细胞浸润并加剧对免疫治疗和常规化疗的耐药性，可能成为 BLCA 的一个有前途的预后因素。