Abstract
BackgroundAerobic glycolysis and epidermal–mesenchymal transition (EMT) play key roles in the development of bladder cancer. This study aimed to investigate the function and the underlying mechanism of dihydropyrimidinase like 2 (DPYSL2) in bladder cancer progression.MethodsThe expression pattern of DPYSL2 in bladder cancer and the correlation of DPYSL2 expression with clinicopathological characteristics of bladder cancer patients were analyzed using the data from different databases and tissue microarray. Gain- and loss-of-function assays were performed to explore the role of DPYSL2 in bladder cancer progression in vitro and in mice. Proteomic analysis was performed to identify the interacting partner of DPYSL2 in bladder cancer cells.FindingsThe results showed that DPYSL2 expression was upregulated in bladder cancer tissue compared with adjacent normal bladder tissue and in more aggressive cancer stages compared with lower stages. DPYSL2 promoted malignant behavior of bladder cancer cells in vitro, as well as tumor growth and distant metastasis in mice. Mechanistically, DPYSL2 interacted with pyruvate kinase M2 (PKM2) and promoted the conversion of PKM2 tetramers to PKM2 dimers. Knockdown of PKM2 completely blocked DPYSL2-induced enhancement of the malignant behavior, glucose uptake, lactic acid production, and epithelial–mesenchymal transition in bladder cancer cells.InterpretationIn conclusion, the results suggest that DPYSL2 promotes aerobic glycolysis and EMT in bladder cancer via PKM2, serving as a potential therapeutic target for bladder cancer treatment.
Highlights
Despite recent diagnostic and therapeutic advances, the incidence and mortality of bladder cancer are increasing worldwide
By analyzing the GSE89 and GSE32548 datasets from the Gene Expression Omnibus (GEO) database, we found that dihydropyrimidinase like 2 (DPYSL2) mRNA levels were significantly increased in the bladder tumor tissue samples from patients with muscular invasive bladder cancer (MIBC) compared with those from patients with non-muscular invasive bladder cancer (NMIBC) (Figures 1A,B)
DPYSL2 bound to pyruvate kinase M2 (PKM2) and blocked the formation of highly catalytic PKM2 tetramer, which in turn promotes anaerobic glycolysis and epidermal–mesenchymal transition (EMT) in bladder cancer cells
Summary
Despite recent diagnostic and therapeutic advances, the incidence and mortality of bladder cancer are increasing worldwide. In 2012, 430,000 new cases of bladder cancer have been reported worldwide, with 160,000 deaths (Antoni et al, 2017); in 2018, the number of new cases has increased to 549,393, with 199,922 deaths (Bladder Source Globocan, 2018). It is urgent to reveal the mechanisms underlying bladder cancer progression and to find new therapeutic targets for bladder cancer treatment. Epithelial–mesenchymal transition (EMT) is closely related to cancer progression by enhancing cancer motility and dissemination through the disruption of intercellular junctions (Nieto et al, 2016). Aerobic glycolysis and epidermal–mesenchymal transition (EMT) play key roles in the development of bladder cancer. This study aimed to investigate the function and the underlying mechanism of dihydropyrimidinase like 2 (DPYSL2) in bladder cancer progression
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