Derlin-1 overexpression confers poor prognosis in muscle invasive bladder cancer and contributes to chemoresistance and invasion through PI3K/AKT and ERK/MMP signaling.

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.

• Authors: Qianze Dong, Lin Fu, Yue Zhao, Shutao Tan, Enhua Wang
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 10 Pg. 17059-17069 (Mar 07 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28178653 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• DERL1 protein, human
• Membrane Proteins
• Proto-Oncogene Proteins c-bcl-2
• Class Ia Phosphatidylinositol 3-Kinase
• Proto-Oncogene Proteins c-akt
• Matrix Metalloproteinases
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9
• Cisplatin

Topics

• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Class Ia Phosphatidylinositol 3-Kinase (metabolism)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Female
• Humans
• Kaplan-Meier Estimate
• MAP Kinase Signaling System
• Male
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Matrix Metalloproteinases (metabolism)
• Membrane Proteins (genetics, metabolism)
• Middle Aged
• Muscles (metabolism, pathology)
• Neoplasm Invasiveness
• Phosphorylation
• Prognosis
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• RNA Interference
• Signal Transduction
• Urinary Bladder Neoplasms (drug therapy, genetics, metabolism)