title: The prognostic significance of DAPK1 in bladder cancer.
abstract: Bladder cancer is one of the leading causes of cancer-related death in men, however, there was only limited effective treatment for invasive bladder cancer. DAPK1 has been shown to play important role in apoptosis and autophagy to suppress cancer progression. Previous results have shown that DAPK1 promoter was hypermethylated in the majority of bladder cancer specimens, however, the prognostic significance of DAPK1 in bladder cancer has yet to be demonstrated. In the present study, we found that DAPK1 expression was negatively associated with tumor stage and a low level expression of DAPK1 in bladder cancer specimens were associated with shorter survival in bladder cancer patients in 3 independent bladder cancer datasets (n = 462). Further investigation showed that FGFR3 knockdown resulted in downregulation of DAPK1 in bladder cancer cell line, suggesting that FGFR3 may be an upstream factor of DAPK1. Further analysis of the 3 independent bladder cancer datasets have identified ACOX1, UPK2, TRAK1, PLEKHG6 and MT1X genes had their expression significantly correlated with that of DAPK1. Knockdown of DAPK1 in bladder cancer T24 cells resulted in downregulation of ACOX1, UPK2 and TRAK1. Interestingly, TRAK1, by itself, was a favorable prognostic marker in the 3 independent bladder cancer datasets. Importantly, by using connectivity mapping with DAPK1-associated gene signature, we found that vemurafenib and trametinib could possibly reverse DAPK1-associated gene signature, suggesting that inhibition of Raf/MEK pathway may be a potential therapeutic approach for bladder cancer. Indeed, treatment of vemurafenib in T24 bladder cancer cells resulted in upregulation of DAPK1 confirming our connectivity mapping, while knockdown of DAPK1 resulted in reduced sensitivity towards inhibition of Braf signaling by vemurafenib. Together, our results suggest that DAPK1 is an important prognostic marker and therapeutic target for bladder cancer and have identified possible therapeutic agents for future testing in bladder cancer models with low DAPK1 expression.
authors.affiliation: Department of Urology, The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, People's Republic of China.
authors.forename: Jian-Yun
authors.initials: JY
authors.lastname: Xie
authors.affiliation: College of Life Sciences, Fujian Normal University, Fuzhou, Fujian Province, People's Republic of China.
authors.forename: Peng-Chen
authors.initials: PC
authors.lastname: Chen
authors.affiliation: Department of Urology, The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, People's Republic of China.
authors.forename: Jia-Li
authors.initials: JL
authors.lastname: Zhang
authors.affiliation: Department of Urology, The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, People's Republic of China.
authors.forename: Ze-Shou
authors.initials: ZS
authors.lastname: Gao
authors.affiliation: Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR.
authors.forename: Henrique
authors.initials: H
authors.lastname: Neves
authors.affiliation: Northern Ireland Centre for Stratified Medicine, University of Ulster, C-TRIC Building, Altnagelvin Hospital Campus, Glenshane Road, Londonderry, United Kingdom.
authors.forename: Shu-Dong
authors.initials: SD
authors.lastname: Zhang
authors.affiliation: Centre for Cancer Research & Cell Biology, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wen
authors.affiliation: Department of Urology, The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, People's Republic of China.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Chen
authors.affiliation: Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR.
authors.forename: Hang Fai
authors.initials: HF
authors.lastname: Kwok
authors.affiliation: College of Life Sciences, Fujian Normal University, Fuzhou, Fujian Province, People's Republic of China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Lin
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D064550:Death-Associated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases