Methylation of S100A8 is a promising diagnosis and prognostic marker in hepatocellular carcinoma

// Kun Liu 1, 5, * , Yuening Zhang 1, * , Chengdong Zhang 1, 6, * , Qinle Zhang 2, * , Jiatong Li 1, * , Feifan Xiao 1 , Yingfang Li 3 , Ruoheng Zhang 1 , Dongwei Dou 1 , Jiezhen Liang 4 , Jian Qin 7 , Zhidi Lin 1 , Dong Zhao 1 , Min Jiang 1 , Zhenxin Liang 1 , Jie Su 8 , Vanaparthy Pranay Gupta 1 , Min He 7 , Xiaoli Yang 1 1 Medical Scientific Research Center, Guangxi Medical University, Nanning, Guangxi 530021, China 2 Genetic and Metabolic Central Laboratory, The Maternal and Children Health Hospital of Guangxi, Guangxi 530002, China 3 Department of Endocrinology, Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, 545005, China 4 Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Guangxi 530021, China 5 Department of Gastroenterology, The Third Hospital of Nanchang City, Jiangxi 330009, China 6 Department of Microbiology and Microbial Engineering, School of Life Sciences, Fudan University, Shanghai 200438, China 7 School of Public Health, Guangxi Medical University, Guangxi 530021, China 8 Key Laboratory of Early Prevention and Treatment for Regional High Frequency, Ministry of Education, Guangxi Medical University, Nanning, Guangxi 530021, China * These authors have contributed equally to this work Correspondence to: Xiaoli Yang, email: cncsyxl@126.com Min He, email: hemin@gxmu.edu.cn Keywords: hepatocellular carcinoma, S100A8, DNA methylation, pyrosequencing, prognosis Received: October 03, 2015     Accepted: June 29, 2016     Published: July 23, 2016 ABSTRACT The abnormality of DNA methylation is one of the major epigenetic alterations in the human hepatocellular carcinoma (HCC). We have assessed the global genomic DNA methylation profiles in human HCC patients by using the Infinium Human Methylation27 BeadChip. A CpG loci of S100A8 was found to be significantly hypomethylated in HCC. Pooled meta-analysis of five validation public datasets demonstrated its methylation level was significantly lower for HCC compared to paired adjacent normal tissues. Quantitative pyrosequencing analysis also showed that the S100A8 methylation level was decreased in cancer tissues (31.90%±13.31%) than that in the paired adjacent normal tissues (65.33%±3.64%, p <0.01). The area under the ROC curve (AUC) value was 0.950 ( p <0.01). Kaplan-Meier survival curves revealed that hypomethylation of S100A8 was associated with shortened overall survival (OS) and progression-free survival (PFS) (log rank p <0.05). Multivariate Cox proportional hazards model also indicated significantly shorter OS (HR, 1.709; 95 % CI, 1.127–2.591) and PFS (HR, 1.767; 95 % CI, 1.168–2.974) were observed in the low-methylation-level group compared to the high-methylation-level group. Furthermore, S100A8 overexpression in Huh7 and MHCC-97H hepatoma cell lines led to increased cell proliferation, migration, invasion, and tumor growth. These findings suggested S100A8 methylation to be served as potential diagnosis and prognosis marker for HCC. S100A8 also may play as a tumor promoter in HCC.