BIN1 inhibited tumor growth, metastasis and stemness by ALDH1/NOTCH pathway in bladder carcinoma.

IF 2.7 3区 生物学
Si-Yu Chen, Ya-Long Zhang, Xiao-Ran Li, Ji-Rong Wang, Kun-Peng Li, Shun Wan, Jian-Wei Yang, Hao Wang, Jin-Long Cao, Chen-Yang Wang, Xin-Peng Fan, Sheng-Jun Fu, Li-Yun Ding, Tuan-Jie Che, Li Yang
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引用次数: 0

Abstract

Background: Bladder cancer (BLCA) represents one of the most prevalent urological malignancies worldwide. Bridging integrator 1 (BIN1), a well-characterized tumor suppressor that interacts with and inhibits oncogenic Myc transcription factors, has demonstrated crucial roles in various cancer types. However, its specific functions and underlying molecular mechanisms in BLCA development and progression remain poorly understood. This study aims to elucidate the role of BIN1 in regulating BLCA cell proliferation, metastasis, and cancer stem cell properties.

Methods: Using urinary proteomics analysis, we identified BIN1 as a significantly dysregulated protein in BLCA. The clinical significance of BIN1 was further validated through comprehensive analyses of public databases. BIN1 expression levels defined distinct molecular and immunological subtypes of BLCA. Through proteomic profiling of BIN1-overexpressing UMUC3 cells and corresponding controls, we identified ALDH1 as a key downstream effector in the BIN1-regulated ALDH1/NOTCH signaling axis. We employed multiple experimental approaches, including Western blot analysis, quantitative RT-PCR, immunofluorescence staining, wound healing assays, transwell migration assays, colony formation assays, tumor sphere formation assays, flow cytometry, CCK8 proliferation assays, and cell transfection experiments.

Results: We observed significant downregulation of BIN1 in both BLCA tissues and cell lines compared to normal adjacent tissues and SV-HUC-1 cells, respectively. BIN1 overexpression inhibited cancer cell proliferation by promoting apoptosis and suppressed epithelial-mesenchymal transition (EMT), thereby reducing local invasion and distant metastasis. Additionally, BIN1 regulated cancer stem cell properties through modulation of ALDH1 expression, with NOTCH2 acting as a crucial downstream mediator of ALDH1 signaling.

Conclusion: Our findings demonstrate that BIN1 functions as a tumor suppressor in BLCA and suggest its potential utility as both a diagnostic biomarker and therapeutic target for BLCA treatment.

BIN1通过ALDH1/NOTCH通路抑制膀胱癌肿瘤的生长、转移和干性。
背景:膀胱癌(BLCA)是全球最常见的泌尿系统恶性肿瘤之一。桥接整合子1 (BIN1)是一种具有良好特征的肿瘤抑制因子,可与致癌Myc转录因子相互作用并抑制其活性,在多种癌症类型中发挥重要作用。然而,其在BLCA发生和发展中的具体功能和潜在的分子机制仍然知之甚少。本研究旨在阐明BIN1在调节BLCA细胞增殖、转移和肿瘤干细胞特性中的作用。方法:通过尿蛋白组学分析,我们发现BIN1是BLCA中一个显著失调的蛋白。通过对公共数据库的综合分析,进一步验证BIN1的临床意义。BIN1的表达水平定义了不同的BLCA分子和免疫学亚型。通过对bin1过表达的UMUC3细胞和相应对照的蛋白质组学分析,我们发现ALDH1是bin1调控的ALDH1/NOTCH信号轴的关键下游效应因子。我们采用了多种实验方法,包括Western blot分析、定量RT-PCR、免疫荧光染色、伤口愈合试验、transwell迁移试验、菌落形成试验、肿瘤球形成试验、流式细胞术、CCK8增殖试验和细胞转染实验。结果:与正常相邻组织和SV-HUC-1细胞相比,我们观察到BLCA组织和细胞系中BIN1的表达均显著下调。BIN1过表达通过促进细胞凋亡和抑制上皮-间质转化(epithelial- mesenchal transition, EMT)来抑制癌细胞增殖,从而减少局部侵袭和远处转移。此外,BIN1通过调节ALDH1的表达来调节癌症干细胞的特性,NOTCH2作为ALDH1信号传导的重要下游介质。结论:我们的研究结果表明BIN1在BLCA中具有肿瘤抑制作用,并提示其作为BLCA治疗的诊断生物标志物和治疗靶点的潜在用途。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Hereditas
Hereditas Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
3.80
自引率
3.70%
发文量
0
期刊介绍: For almost a century, Hereditas has published original cutting-edge research and reviews. As the Official journal of the Mendelian Society of Lund, the journal welcomes research from across all areas of genetics and genomics. Topics of interest include human and medical genetics, animal and plant genetics, microbial genetics, agriculture and bioinformatics.
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