Abstract
Although GC (gemcitabine and cisplatin) chemotherapy remains an effective method for treating bladder cancer (BCa), chemoresistance is a major obstacle in chemotherapy. In this study, we determined whether gemcitabine resistance correlates with migratory/invasive potential in BCa and whether this relationship is regulated by the cylindromatosis (CYLD)-Livin module. First, we independently investigated the correlation of CYLD/Livin and gemcitabine resistance with the potential for tumor migration and invasiveness. Second, we found that co-transfected CYLD and Livin dramatically improved sensitivity to gemcitabine chemotherapy and decreased migration/invasion potential. Next, we determined that CYLD may regulate Livin by the NF-κB-dependent pathway. We also found that CYLD overexpression and Livin knockdown might improve gemcitabine chemosensitivity by decreasing autophagy and increasing apoptosis in BCa cells. Finally, the effects of CYLD-Livin on tumor growth in vivo were evaluated. Our study demonstrates that CYLD-Livin might represent a potential therapeutic for chemoresistant BCa.
Keywords:
Autophagy; Bladder cancer (BCa); Cylindromatosis (CYLD); Gemcitabine; Livin.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antimetabolites, Antineoplastic / pharmacology
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Apoptosis / drug effects
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Apoptosis / genetics
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Autophagy / drug effects
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Autophagy / genetics
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Blotting, Western
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Cell Line, Tumor
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Cell Movement / drug effects*
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Cell Movement / genetics
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Cell Survival / drug effects
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Cell Survival / genetics
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Deoxycytidine / analogs & derivatives*
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Deoxycytidine / pharmacology
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Deubiquitinating Enzyme CYLD
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Down-Regulation
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Drug Resistance, Neoplasm / genetics
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Female
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Gemcitabine
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Gene Expression Regulation, Neoplastic
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Humans
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Inhibitor of Apoptosis Proteins / genetics*
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Inhibitor of Apoptosis Proteins / metabolism
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasm Invasiveness
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / metabolism
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / metabolism
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Urinary Bladder Neoplasms / drug therapy*
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Urinary Bladder Neoplasms / genetics
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Urinary Bladder Neoplasms / metabolism
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Xenograft Model Antitumor Assays
Substances
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Adaptor Proteins, Signal Transducing
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Antimetabolites, Antineoplastic
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BIRC7 protein, human
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Inhibitor of Apoptosis Proteins
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Neoplasm Proteins
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Tumor Suppressor Proteins
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Deoxycytidine
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CYLD protein, human
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Deubiquitinating Enzyme CYLD
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Gemcitabine