Xiao Jian-Hua, Xu Li-Zhe, Ning Jin-Zhuo, Cheng Fan
Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, P.R. China; Department of Urology, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang, Hubei Province, P.R. China.
Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, P.R. China.
J Biol Chem. 2025 Feb;301(2):108155. doi: 10.1016/j.jbc.2025.108155. Epub 2025 Jan 4.
Bladder cancer (BCa) is a common and lethal disease characterized by high recurrence rates and limited treatment options. Understanding the molecular pathways of BCa progress is crucial for investigating more effective targeted therapies. While ADAMTS12 is known to contribute to cancer progression and treatment resistance, its prognostic significance and underlying mechanisms in BCa remain poorly understood. To elucidate the molecular pathways and functions of ADAMTS12 in BCa, we employed various experimental approaches, including Transwell invasion assays, flow cytometry analysis, wound-healing assays, CCK-8 assays, and a xenograft tumor model. Our results demonstrated that overexpression of ADAMTS12 significantly enhanced cell growth, migration, and invasion while inhibiting apoptosis through the activation of the FAK/PI3K/AKT signaling pathway. Conversely, the knockdown of ADAMTS12 produced the opposite effects. In vivo studies further confirmed that the inhibition of ADAMTS12 effectively suppressed tumor progression. Comprehensive bioinformatics analysis of the TCGA-BLCA dataset and protein-protein interaction networks revealed a strong positive correlation between COL3A1 and ADAMTS12, identifying COL3A1 as a potential downstream target of ADAMTS12. Additionally, we observed a significant increase in the expression levels of ADAMTS12 and COL3A1 in BCa tissues compared to healthy tissues, as confirmed by Western blotting and qRT-PCR analysis. Notably, inhibition of COL3A1 reversed the enhanced cell growth and invasion associated with ADAMTS12 overexpression and suppressed cell apoptosis. Our findings suggest that ADAMTS12 promotes BCa progression through the FAK/PI3K/AKT signaling pathway by regulating COL3A1, highlighting its potential as a valuable marker for diagnosis and prognosis in BCa.
膀胱癌（BCa）是一种常见的致命疾病，其特征是复发率高且治疗选择有限。了解BCa进展的分子途径对于研究更有效的靶向治疗至关重要。虽然已知ADAMTS12有助于癌症进展和治疗抵抗，但其在BCa中的预后意义和潜在机制仍知之甚少。为了阐明ADAMTS12在BCa中的分子途径和功能，我们采用了多种实验方法，包括Transwell侵袭试验、流式细胞术分析、伤口愈合试验、CCK-8试验和异种移植肿瘤模型。我们的结果表明，ADAMTS12的过表达通过激活FAK/PI3K/AKT信号通路显著增强细胞生长、迁移和侵袭，同时抑制细胞凋亡。相反，ADAMTS12的敲低产生了相反的效果。体内研究进一步证实，抑制ADAMTS12可有效抑制肿瘤进展。对TCGA-BLCA数据集和蛋白质-蛋白质相互作用网络的综合生物信息学分析揭示了COL3A1与ADAMTS12之间存在强正相关，确定COL3A1为ADAMTS12的潜在下游靶点。此外，通过蛋白质印迹和qRT-PCR分析证实，与健康组织相比，BCa组织中ADAMTS12和COL3A1的表达水平显著增加。值得注意的是，抑制COL3A1可逆转与ADAMTS12过表达相关的增强的细胞生长和侵袭，并抑制细胞凋亡。我们的研究结果表明，ADAMTS12通过调节COL3A1促进FAK/PI3K/AKT信号通路中的BCa进展，突出了其作为BCa诊断和预后有价值标志物的潜力。
