Abstract
Derlin-1 has been found to be overexpressed in several human cancers. However, its clinical significance and biological roles in bladder cancer remain unexplored. Here, we found that Derlin-1 was upregulated in 38.6% (58/150) cases of cancer samples. The rate of Derlin-1 overexpression was higher in muscle invasive bladder cancer (MIBC) than non-muscle invasive bladder cancer (NMIBC) (p=0.0079). Derlin-1 was a predicting factor for poor patient prognosis. Derlin-1 depletion inhibited while its overexpression facilitated cell invasion and colony formation. In addition, Derlin-1 overexpression induced cisplatin resistance while its depletion sensitized cancer cells to cisplatin. Further analysis demonstrated that Derlin-1 activated AKT phosphorylation and upregulated Bcl-2 expression. Blockage of AKT signaling by LY294005 abolished the effects of Derlin-1 on Bcl-2 and cisplatin resistance. Immunoprecipitation indicated Derlin-1 interacted with p110α subunit of PI3K. In addition, we showed that Derlin-1 depletion downregulated and its overexpression upregulated cell MMP-2/9 expression and ERK phosphorylation. Derlin-1 mediated upregulation of MMP-2/9 could be blocked by ERK inhibitor. In conclusion, our study demonstrated that Derlin-1 is overexpressed in bladder cancer and promotes malignant phenotype through ERK/MMP and PI3K/AKT/Bcl-2 signaling pathway.
Highlights
Bladder cancer is one of the most common cancers and its incidence is increasing in recent years [1]
We identify www.impactjournals.com/oncotarget elevated expression of Derlin-1 in bladder cancer tissues and cell lines, especially in muscle invasive bladder cancer (MIBC)
We demonstrate that Derlin-1 induces bladder cancer invasion through ERK/ MMP signaling
Summary
Bladder cancer is one of the most common cancers and its incidence is increasing in recent years [1]. The prognosis of bladder cancer lies on its invasion depth, lymph node metastasis and response to chemotherapy [2,3,4]. Development of chemoresistance plays a vital role in the progression and poor response of bladder cancer and identifying of related targets is an important task. Derlin-1 expression is elevated in breast cancer and correlates with tumor grade and lymph node metastasis [8]. Our previous study demonstrated that Derlin-1 is overexpressed in non-small cell lung cancers and promotes invasion through regulation of EGFR activity [12]. These studies indicate that Derlin-1 plays an important role in cancer progression
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