Derlin-1 overexpression confers poor prognosis in muscle invasive bladder cancer and contributes to chemoresistance and invasion through PI3K/AKT and ERK/MMP signaling.
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.
Mesh Terms:
Antineoplastic Agents, Blotting, Western, Cell Line, Tumor, Cisplatin, Class Ia Phosphatidylinositol 3-Kinase, Drug Resistance, Neoplasm, Female, Humans, Kaplan-Meier Estimate, MAP Kinase Signaling System, Male, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Matrix Metalloproteinases, Membrane Proteins, Middle Aged, Muscles, Neoplasm Invasiveness, Phosphorylation, Prognosis, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, RNA Interference, Signal Transduction, Urinary Bladder Neoplasms
Antineoplastic Agents, Blotting, Western, Cell Line, Tumor, Cisplatin, Class Ia Phosphatidylinositol 3-Kinase, Drug Resistance, Neoplasm, Female, Humans, Kaplan-Meier Estimate, MAP Kinase Signaling System, Male, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Matrix Metalloproteinases, Membrane Proteins, Middle Aged, Muscles, Neoplasm Invasiveness, Phosphorylation, Prognosis, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, RNA Interference, Signal Transduction, Urinary Bladder Neoplasms
Oncotarget
Date: Mar. 07, 2017
PubMed ID: 28178653
View in: Pubmed Google Scholar
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