Epigenetic silencing of DUSP9 induces the proliferation of human gastric cancer by activating JNK signaling

Wu,Fang; Lv,Tianmin; Chen,Gang; Ye,Huajun; Wu,Wei; Li,Gang; Zhi,Fa-Chao

doi:10.3892/or.2015.3998

Epigenetic silencing of DUSP9 induces the proliferation of human gastric cancer by activating JNK signaling

Authors:
- Fang Wu
- Tianmin Lv
- Gang Chen
- Huajun Ye
- Wei Wu
- Gang Li
- Fa-Chao Zhi
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Affiliations: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China, Department of Nursing, Medical School, Huzhou Teachers College, Zhejiang, P.R. China, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, P.R. China, Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, P.R. China, Department of Chemoradiation Oncology, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, P.R. China
Published online on: May 20, 2015 https://doi.org/10.3892/or.2015.3998
Pages: 121-128

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Abstract

Dual-specificity phosphatase 9 (DUSP9) is a strong negative regulator of transcription factor activating kinases (ERK, JNK and p38) in the mitogen-activated protein kinase (MAPK) pathways. The aim of this study was to examine the CpG island methylation status of DUSP9 using bisulfite sequencing PCR (BSP) in gastric cancer (GC). The investigation was conducted on 30 clinical GC samples and selected corresponding tumor-free normal gastric mucosa tissues, using BSP for the determination of the promoter methylation status. The methylation status of the tumor samples was compared to the corresponding tumor-free samples. DUSP9 was silenced by promoter region hypermethylation and G2/M phase arrest was induced by DUSP9 in the MKN-1 GC cell line. MKN-1 proliferation was suppressed by DUSP9 by inhibiting c-Jun, which was induced by JNK signaling. The expression levels of CCND1, c-Jun, CDK4 and CDK6 were upregulated while p21 was downregulated by DUSP9 in MKN-1 cells. However, DUSP9-induced resulted in the regulation of the levels of cycle-related molecules, whivh were inhibited when the JNK inhibitor SP600125 was added. In conclusion, DUSP9 was frequently methylated in human GC and the expression of DUSP9 is silenced by promoter region hypermethylation. The results of this study, combined with previous studies, suggested that therapeutic intervention to increase the expression or activity of DUSP9 may enable the activation of anti-proliferation signals in malignant cells.

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