Bladder cancer (BC), the predominant urological malignancy in men, exhibits complex molecular underpinnings contributing to its progression. This investigation aims to elucidate the expression dynamics of calcium‐binding protein 39 (CAB39) in both healthy and cancerous tissues and to explore its functional role in the epithelial–mesenchymal transition (EMT) within human bladder cancer contexts. Utilizing immunohistochemistry and quantitative reverse transcription analyses, we assessed CAB39 expression across BC specimens and cell lines. Further, we implemented wound healing, cell invasion, and CCK‐8 proliferation assays in CAB39‐knockdown cell lines, alongside a nude mouse xenograft model, to gauge the impact of diminished CAB39 expression on the invasive, migratory, and proliferative capacities of BC cells. Our gene set enrichment analysis probed into the repertoire of genes augmented by increased CAB39 expression in BC cells, with subsequent validation via western blotting. Our findings reveal a pronounced overexpression of CAB39 in both BC tissues and cellular models, inversely correlated with disease prognosis. Remarkably, the oncogenic trajectory of bladder cancer was mitigated upon the establishment of shRNA‐mediated CAB39 knockdown in vitro and in vivo, effectively reversing the cancer's invasive and metastatic behaviors and curbing tumorigenesis in xenograft models. Hence, CAB39 emerges as a critical biomarker for bladder cancer progression, significantly implicated in facilitating EMT via the upregulation of neural cadherin (N‐cadherin) and the suppression of epithelial cadherin through NF‐κB signaling pathways. CU‐T12‐9 effectively overturned the downregulation of p65‐NF‐kB and N‐cadherin, key elements involved in EMT and cell motility, induced by CAB39 knockdown. This study underscores CAB39's pivotal role in bladder cancer pathophysiology and its potential as a therapeutic target.

中文翻译：

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CAB39 通过 NF-κB 信号激活调节上皮-间质转化，增强膀胱癌的侵袭和转移


膀胱癌 （BC） 是男性主要的泌尿系统恶性肿瘤，表现出导致其进展的复杂分子基础。本研究旨在阐明钙结合蛋白 39 （CAB39） 在健康和癌组织中的表达动力学，并探索其在人膀胱癌背景下上皮-间质转化 （EMT） 中的功能作用。利用免疫组织化学和定量逆转录分析，我们评估了 BC 标本和细胞系中 CAB39 的表达。此外，我们在 CAB39 敲低细胞系中实施了伤口愈合、细胞侵袭和 CCK-8 增殖测定，以及裸鼠异种移植模型，以衡量 CAB39 表达减少对 BC 细胞侵袭、迁移和增殖能力的影响。我们的基因集富集分析探查了 BC 细胞中 CAB39 表达增加的基因库，随后通过蛋白质印迹进行验证。我们的研究结果显示 CAB39 在 BC 组织和细胞模型中都明显过表达，与疾病预后呈负相关。值得注意的是，在体外和体内建立 shRNA 介导的 CAB39 敲低后，膀胱癌的致癌轨迹得到缓解，有效逆转了癌症的侵袭和转移行为，并抑制了异种移植模型中的肿瘤发生。因此，CAB39 成为膀胱癌进展的关键生物标志物，与通过神经钙粘蛋白 （N-cadherin） 的上调和通过 NF-κB 信号通路抑制上皮钙粘蛋白促进 EMT 显著相关。 CU-T12-9 有效推翻了 CAB39 敲低诱导的 p65-NF-kB 和 N-钙粘蛋白的下调，这些关键元件参与 EMT 和细胞运动。本研究强调了 CAB39 在膀胱癌病理生理学中的关键作用及其作为治疗靶点的潜力。