title: DACT2 is frequently methylated in human gastric cancer and methylation of DACT2 activated Wnt signaling.
abstract: Dapper, Dishevelled-associated antagonist of β-catenin (DACT), is a key regulator of Wnt signaling pathway. The purpose of this study is to explore the epigenetic changes and the function ofDACT2 in human gastric cancer (GC). Eight human gastric cancer cell lines, 167 cases of primary gastric cancer and 8 cases of normal gastric mucosa were involved in this study. In addition, methylation Specific PCR (MSP), semi-quantitative RT-PCR, colony formation assay, flow cytometry assay, siRNA, immunofluorescence techniques and xenograft mice models were employed. The results indicate that DACT2 is frequently methylated in human primary gastric cancer (55.7%), and that methylation of DACT2 is associated with lost or reduction in its expression (X(2) test, P<0.01). We found that DACT2 expression was regulated by promoter region hypermethylation. Methylation of DACT2 is associated with tumor differentiation, invasion and intravascular cancerous emboli (X(2) test, P<0.05, P<0.05 and P<0.05). In gastric cancer patients treated with 5-FU and cisplatin, the five-year survival rates are higher in DACT2 methylated cases. DACT2 inhibits cell proliferation, migration and invasion in gastric cancer cells and suppresses gastric cancer xenografts in mice. Restoration of DACT2 expression inhibits both canonical and noncanonical WNT signaling in SGC7901 cells. Restoration of DACT2 expression sensitized gastric cancer cells to paclitaxel and 5-FU. In conclusion, DACT2 is frequently methylated in human gastric cancer and DACT2 expression is silenced by promoter region hypermethylation. DACT2 suppressed gastric cancer proliferation, invasion and metastasis by inhibiting Wnt signaling both in vitro and in vivo.
authors.affiliation: Department of Gastroenterology and Hepatology, Chinese PLA General Hospital #28 Fuxing Road, Beijing 100853, China ; Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University 324 Jingwu Weiqi Road, Jinan, 250021, China.
authors.forename: Yuanzi
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Gastroenterology and Hepatology, Chinese PLA General Hospital #28 Fuxing Road, Beijing 100853, China.
authors.forename: Wenji
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Gastroenterology and Hepatology, Chinese PLA General Hospital #28 Fuxing Road, Beijing 100853, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology and Hepatology, Chinese PLA General Hospital #28 Fuxing Road, Beijing 100853, China ; Breast Cancer Medical Oncology, Tianjin Medical University Cancer Institute and Hospital Huan-Hu-Xi Road, Tianjin 300060, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Gastroenterology and Hepatology, Chinese PLA General Hospital #28 Fuxing Road, Beijing 100853, China ; Medical College of NanKai University #94 Weijin Road, Tianjin 300071, China.
authors.forename: Baoping
authors.initials: B
authors.lastname: Cao
authors.affiliation: Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine #800 Dongchuan Road, Shanghai, 200240, China.
authors.forename: Yingyan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Beijing Institute for Cancer Research, Peking University School of Oncology Beijing 100034, China.
authors.forename: Youyong
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University #1650 Orleans Street, Baltimore, Maryland, 21231, USA.
authors.forename: Malcolm V
authors.initials: MV
authors.lastname: Brock
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University #1650 Orleans Street, Baltimore, Maryland, 21231, USA.
authors.forename: Jame G
authors.initials: JG
authors.lastname: Herman
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University #1650 Orleans Street, Baltimore, Maryland, 21231, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Licchesi
authors.affiliation: Department of Gastroenterology and Hepatology, Chinese PLA General Hospital #28 Fuxing Road, Beijing 100853, China.
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology and Hepatology, Chinese PLA General Hospital #28 Fuxing Road, Beijing 100853, China.
authors.forename: Mingzhou
authors.initials: M
authors.lastname: Guo
keywords: DACT2; DNA methylation; Gastric cancer; Wnt signaling pathway; chemo-sensitivity