title: CYLD downregulates Livin and synergistically improves gemcitabine chemosensitivity and decreases migratory/invasive potential in bladder cancer: the effect is autophagy-associated.
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.
authors.affiliation: Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jingwu Road, No 324, Jinan, 250021, Shandong, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jingwu Road, No 324, Jinan, 250021, Shandong, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Digestive Diseases, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China.
authors.forename: Chensheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jingwu Road, No 324, Jinan, 250021, Shandong, China.
authors.forename: Sentai
authors.initials: S
authors.lastname: Ding
authors.affiliation: Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jingwu Road, No 324, Jinan, 250021, Shandong, China.
authors.forename: Dongbin
authors.initials: D
authors.lastname: Bi
authors.affiliation: Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jingwu Road, No 324, Jinan, 250021, Shandong, China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Niu
authors.affiliation: Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Han
authors.affiliation: Shandong University, Jinan, 250000, China.
authors.forename: Wenjia
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jingwu Road, No 324, Jinan, 250021, Shandong, China.
authors.forename: Dexuan
authors.initials: D
authors.lastname: Gao
authors.affiliation: Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jingwu Road, No 324, Jinan, 250021, Shandong, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jingwu Road, No 324, Jinan, 250021, Shandong, China. kyoto2310@sina.com.
authors.forename: Jiaju
authors.initials: J
authors.lastname: Lu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000074749:Deubiquitinating Enzyme CYLD; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000964:Antimetabolites, Antineoplastic; C419866:BIRC7 protein, human; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; D000093542:Gemcitabine
keywords: Autophagy; Bladder cancer (BCa); Cylindromatosis (CYLD); Gemcitabine; Livin