Quantitative proteomics identifies TUBB6 as a biomarker of muscle‐invasion and poor prognosis in bladder cancer

膀胱癌 生物标志物 免疫组织化学 组织微阵列 肿瘤科 医学 癌症研究 生物标志物发现 蛋白质组学 癌症 病理 生物 内科学 基因 生物化学
作者
Bohyun Kim,Minsun Jung,Kyung Chul Moon,Dohyun Han,Kwangsoo Kim,Hyeyoon Kim,Sunah Yang,Dongjoo Lee,Hyeji Jun,Kyung‐Min Lee,Cheng Hyun Lee,Ilias P. Nikas,Sohyeon Yang,Hyebin Lee,Han Suk Ryu
出处
期刊:International Journal of Cancer [Wiley]
卷期号:152 (2): 320-330 被引量:12
标识
DOI:10.1002/ijc.34265
摘要

Muscle-invasive urothelial carcinoma (MIUC) of the bladder shows highly aggressive tumor behavior, which has prompted the quest for robust biomarkers predicting invasion. To discover such biomarkers, we first employed high-throughput proteomic method and analyzed tissue biopsy cohorts from patients with bladder urothelial carcinoma (BUC), stratifying them according to their pT stage. Candidate biomarkers were selected through bioinformatic analysis, followed by validation. The latter comprised 2D and 3D invasion and migration assays, also a selection of external public datasets to evaluate mRNA expression and an in-house patient-derived tissue microarray (TMA) cohort to evaluate protein expression with immunohistochemistry (IHC). Our multilayered platform-based analysis identified tubulin beta 6 class V (TUBB6) as a promising prognostic biomarker predicting MIUC of the bladder. The in vitro 2D and 3D migration and invasion assays consistently showed that inhibition of TUBB6 mRNA significantly reduced cell migration and invasion ability in two BUC cell lines with aggressive phenotype (TUBB6 migration, P = .0509 and P < .0001; invasion, P = .0002 and P = .0044; TGFBI migration, P = .0214 and P = .0026; invasion, P < .0001 and P = .0001; T24 and J82, respectively). Validation through multiple public datasets, including The Cancer Genome Atlas (TCGA) and selected GSE (Genomic Spatial Event) databases, confirmed TUBB6 as a potential biomarker predicting MIUC. Further protein-based validation with our TMA cohort revealed concordant results, highlighting the clinical implication of TUBB6 expression in BUC patients (overall survival: P < .001). We propose TUBB6 as a novel IHC biomarker to predict invasion and poor prognosis, also select the optimal treatment in BUC patients.
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