Abstract
Bladder carcinoma is highly heterogeneous and its complex molecular landscape; thus, poses a significant challenge for resolving an effective treatment in metastatic tumors. We computed the epithelial-mesenchymal transition (EMT) scores of three bladder carcinoma subtypes—luminal, basal, and non-type. The EMT score of the non-type indicated a “mesenchymal-like” phenotype, which correlates with a relatively more aggressive form of carcinoma, typified by an increased migration and invasion. To identify the altered signaling pathways potentially regulating this EMT phenotype in bladder cancer cell lines, we utilized liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based phosphoproteomic approach. Bioinformatics analyses were carried out to determine the activated pathways, networks, and functions in bladder carcinoma cell lines. A total of 3125 proteins were identified, with 289 signature proteins noted to be differentially phosphorylated (p ≤ 0.05) in the non-type cell lines. The integrin pathway was significantly enriched and five major proteins (TLN1, CTTN, CRKL, ZYX and BCAR3) regulating cell motility and invasion were hyperphosphorylated. Our study reveals GSK3A/B and CDK1 as promising druggable targets for the non-type molecular subtype, which could improve the treatment outcomes for aggressive bladder carcinoma.
Highlights
Advanced cancer therapeutics demands a detailed understanding of the altered mechanisms operating in malignant disease
To compute the epithelial-mesenchymal transition (EMT) score in bladder carcinoma cell lines, we adopted a similar approach to that used in single sample gene set enrichment analysis (ssGSEA) [22]
EMT scores suggested that non-type cell lines were “mesenchymal-like”, whereas the luminal and basal cell lines had an “epithelial-like” characteristic (Figure 1a)
Summary
Advanced cancer therapeutics demands a detailed understanding of the altered mechanisms operating in malignant disease. In bladder carcinoma, the current treatment regimens and interventions are mostly determined by the clinicopathological characteristics of the tumor. Bladder carcinoma is categorized into two clinicopathologically distinct subgroups: non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). 75% of bladder carcinoma is NMIBC, whereas 20% to 25% is MIBC. About 50% to 70% of NMIBC, including Ta- and T1-stage tumors, frequently recur [1], whereas 10% to 15% progress to MIBC (T2, T3, and T4 stages) [2]. Emerging evidence suggests that tumor heterogeneity alters treatment response and confers resistance, leading to recurrence. A detailed understanding of the clinicopathological subgroups and their molecular alterations is of paramount interest, especially for targeted therapy. Identification of distinct molecular subtypes of NMIBC and MIBC could highlight clinically relevant signaling pathways
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