DAPK1 as an independent prognostic marker in liver cancer

Ling Li; Libin Guo; Qingshui Wang; Xiaolong Liu; Yongyi Zeng; Qing Wen; Shudong Zhang; Hang Fai Kwok; Yao Lin; Jingfeng Liu

doi:10.7717/peerj.3568

DAPK1 as an independent prognostic marker in liver cancer

PeerJ. 2017 Jul 19:5:e3568. doi: 10.7717/peerj.3568. eCollection 2017.

Authors

Ling Li^{1

2}, Libin Guo^{3

4}, Qingshui Wang^{3

4}, Xiaolong Liu², Yongyi Zeng², Qing Wen⁵, Shudong Zhang⁶, Hang Fai Kwok³, Yao Lin⁴, Jingfeng Liu^{1

2}

Affiliations

¹ Hepatopancreatobiliary Surgery Department, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China.
² United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China.
³ Faculty of Health Sciences, University of Macau, Taipa, Macau.
⁴ College of Life Sciences, Fujian Normal University, Fuzhou, Fujian Province, China.
⁵ Centre for Cancer Research & Cell Biology, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom.
⁶ Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute, University of Ulster, Londonderry, United Kingdom.

Abstract

The death-associated protein kinase 1 (DAPK1) can act as an oncogene or a tumor suppressor gene depending on the cellular context as well as external stimuli. Our study aims to investigate the prognostic significance of DAPK1 in liver cancer in both mRNA and protein levels. The mRNA expression of DAPK1 was extracted from the Gene Expression Omnibus database in three independent liver cancer datasets while protein expression of DAPK1 was detected by immunohistochemistry in our Chinese liver cancer patient cohort. The associations between DAPK1 expression and clinical characteristics were tested. DAPK1 mRNA expression was down-regulated in liver cancer. Low levels of DAPK1 mRNA were associated with shorter survival in a liver cancer patient cohort (n = 115; p = 0.041), while negative staining of DAPK1 protein was significantly correlated with shorter time to progression (p = 0.002) and overall survival (p = 0.02). DAPK1 was an independent prognostic marker for both time to progression and overall survival by multivariate analysis. Liver cancer with the b-catenin mutation has a lower DAPK1 expression, suggesting that DAPK1 may be regulated under the b-catenin pathway. In addition, we also identified genes that are co-regulated with DAPK1. DAPK1 expression was positively correlated with IRF2, IL7R, PCOLCE and ZBTB16, and negatively correlated with SLC16A3 in both liver cancer datasets. Among these genes, PCOLCE and ZBTB16 were significantly down-regulated, while SLC16A3 was significantly upregulated in liver cancer. By using connectivity mapping of these co-regulated genes, we have identified amcinonide and sulpiride as potential small molecules that could potentially reverse DAPK1/PCOLCE/ZBTB16/SLC16A3 expression. Our study demonstrated for the first time that both DAPK1 mRNA and protein expression levels are important prognostic markers in liver cancer, and have identified genes that may contribute to DAPK1-mediated liver carcinogenesis.

Keywords: DAPK1; IHC; Liver cancer; Prognosis; Survival.

Grants and funding

This work was supported by the International S&T Cooperation Program of China (2016YFE0121900), the Science and Technology Development Fund of Macau SAR (FDCT 023/2015/AMJ), the National Natural Science Foundation of China (31640053), the Natural Science Foundation of Fujian Province (2016Y0029), the Science and Technology Bureau of Fuzhou City (2014-S-139-7) and the Open Scientific Foundation of Fujian Key Laboratory (2014ZDSY2002). Libin Guo received a PhD studentship from the Faculty Health Sciences University of Macau. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.