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The prognostic significance of DAPK1 in bladder cancer
Xie, Jian-Yun1; Chen, Peng-Chen2; Zhang, Jia-Li1; Gao, Ze-Shou1; Neves, Henrique3; Zhang, Shu-Dong4; Wen, Qing5; Chen, Wei-Dong1; Kwok, Hang Fai3; Lin, Yao2
2017-04-07
Source PublicationPLOS ONE
ISSN1932-6203
Volume12Issue:4
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.

DOIhttps://doi.org/10.1371/journal.pone.0175290
URLView the original
Indexed BySCI
Language英语
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000399375800036
PublisherPUBLIC LIBRARY SCIENCE
The Source to ArticleWOS
Fulltext Access
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Cited Times [WOS]:8   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorChen, Wei-Dong; Kwok, Hang Fai; Lin, Yao
Affiliation1.Department of Urology, The Affiliated People’s Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, People’s Republic of China
2.College of Life Sciences, Fujian Normal University, Fuzhou, Fujian Province, People’s Republic of China
3.Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR
4.Northern Ireland Centre for Stratified Medicine, University of Ulster, C-TRIC Building, Altnagelvin Hospital Campus, Glenshane Road, Londonderry, United Kingdom
5.Centre for Cancer Research & Cell Biology, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, United Kingdom
Corresponding Author AffilicationFaculty of Health Sciences
Recommended Citation
GB/T 7714
Xie, Jian-Yun,Chen, Peng-Chen,Zhang, Jia-Li,et al. The prognostic significance of DAPK1 in bladder cancer[J]. PLOS ONE,2017,12(4).
APA Xie, Jian-Yun.,Chen, Peng-Chen.,Zhang, Jia-Li.,Gao, Ze-Shou.,Neves, Henrique.,...&Lin, Yao.(2017).The prognostic significance of DAPK1 in bladder cancer.PLOS ONE,12(4).
MLA Xie, Jian-Yun,et al."The prognostic significance of DAPK1 in bladder cancer".PLOS ONE 12.4(2017).
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