Candidate tumor suppressor ZNF154 suppresses invasion and metastasis in NPC by inhibiting the EMT via Wnt/β-catenin signalling
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Ying Hu1,3,*, Min-Fang Qi2,*, Qian-Lan Xu1, Xiang-Yun Kong1, Rui Cai1, Qiu-Qiu Chen1, Hua-Ying Tang1 and Wei Jiang1
1Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, Guilin 541001, P.R. China
2Department of Pathology, The 181st Hospital of People's Liberation Army, Guilin 541001, P.R. China
3Department of Oncology, Xianning Central Hospital, The First Affiliated Hospital of Hubei University of Science and Technology, Xianning 437100, P.R. China
*These authors have contributed equally to this work
Wei Jiang, email: [email protected]
Keywords: nasopharyngeal carcinoma, zinc finger protein 154, candidate tumor suppressor, methylation
Received: April 18, 2017 Accepted: July 25, 2017 Published: August 24, 2017
Background: Nasopharyngeal carcinoma (NPC) is especially prevalent in southeast Asia and southern China, but its molecular mechanisms remain poorly characterized. DNA methylation is associated with initiation and progression of tumors, including NPC. Through a genome-wide DNA methylation screening approach, we discovered ZNF154, but its methylation status and roles in NPC have not been investigated.
Methods: The methylation status of ZNF154 in NPC was detected with Methylation specific-PCR (MSP) and Quantitative Sequenom MassARRAY. The invasion and migration capacities were examined by wound healing and transwell invasion assays. The role of ZNF154 in NPC metastasis was clarified with experimental metastasis assay in vivo. Western blotting analysis was used to investigate protein changes followed by ZNF154 over-expression. Kaplan-Meier analysis was performed to determine the association between ZNF154 methylation and prognosis in NPC.
Results: Compared to immortalized nasopharyngeal tissues and cells, ZNF154 expression was frequently downregulated in NPC tissues and cell lines due to promoter methylation. Demethylation treatment with 5-aza-2-deoxycytidine (5-Aza) restored ZNF154 expression in NPC cell lines. Ectopic overexpression of ZNF154 in NPC cells inhibited cell migration and invasion in vitro and lung nodule formation in an in vivo tumor metastasis assay. Mechanistic investigations suggested ZNF154 inhibits Wnt/β-catenin signalling pathway activation and prevents the EMT in NPC. Furthermore, Kaplan-Meier analysis showed hypermethylation of the ZNF154 promoter was associated with significantly poorer disease-free survival (P = 0.032) and distant metastasis-free survival (P = 0.040) among patients with locoregionally advanced NPC.
Conclusions: Taken together, these findings define a novel role for ZNF154 as a tumor suppressor in NPC.
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