Le Wang1,2, Hao Wang2, Xianglong Duan3,4, Penggao Dai5, Jianping Li6. 1. Department of Oncology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China. 2. National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, No. 229 North Taibai Road, Xi'an, 710000, China. 3. The Second Department of General Surgery, Shaanxi Provincial People's Hospital, Xi'an, China. 4. Department of General Surgery, The First Hospital of Yulin, Shaanxi, China. 5. National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, No. 229 North Taibai Road, Xi'an, 710000, China. daipg@nwu.edu.cn. 6. Department of Otolaryngology, Xi'an No.4 Hospital, No. 21 Jiefang Road, Xi'an, 710004, Shaanxi, China. OCTVER@163.com.
Abstract
BACKGROUND: Previous studies showed that dysregulation of Wnt signaling by gene mutation and abnormal gene expression is one of the causative factors for gastric cancer (GC). So far, a systematic and comprehensive analysis of gene mutation, gene expression, and DNA methylation profiles of the Wnt pathway associated with gastric carcinogenesis, however, has not yet been reported. AIMS: To this end, we investigated all the above-mentioned genetic alterations associated with the canonical and non-canonical Wnt pathways in GC tumors, in order to understand the molecular mechanism underlying gastric carcinogenesis. METHODS: The information on gene mutations and expression was obtained from data resources, such as TCGA, GSEA, and TCGA-STAD, and was analyzed with the cBioPortal platform. We also performed in vitro analysis on DDK2 gene, a Wnt inhibitor, to characterize its role in GC tumor cells. RESULTS: We found that gene mutations of 43 Wnt genes and abnormal expression of 13 Wnt genes occurred at a high frequency in GC tumors, and gene amplification and deletion are the major mutation types. Clusters of DNA methylation associated with Wnt signaling genes and GC tumors were also revealed, and a significant increase in β-catenin activity was found in the hypermethylated group of GC tumors. In addition, overexpression of DKK2 gene significantly inhibited multiple biological processes of the GC cells, including their growth, clonal forming, migration, and invasion ability, and induced apoptosis of the GC cells. CONCLUSIONS: Our current study suggested that gene mutation, abnormal gene expression, and altered DNA methylation profiles associated with the Wnt signaling may play an important role in gastric carcinogenesis, and DKK2 gene may act as a tumor suppressor in gastric cells.
BACKGROUND: Previous studies showed that dysregulation of Wnt signaling by gene mutation and abnormal gene expression is one of the causative factors for gastric cancer (GC). So far, a systematic and comprehensive analysis of gene mutation, gene expression, and DNA methylation profiles of the Wnt pathway associated with gastric carcinogenesis, however, has not yet been reported. AIMS: To this end, we investigated all the above-mentioned genetic alterations associated with the canonical and non-canonical Wnt pathways in GC tumors, in order to understand the molecular mechanism underlying gastric carcinogenesis. METHODS: The information on gene mutations and expression was obtained from data resources, such as TCGA, GSEA, and TCGA-STAD, and was analyzed with the cBioPortal platform. We also performed in vitro analysis on DDK2 gene, a Wnt inhibitor, to characterize its role in GC tumor cells. RESULTS: We found that gene mutations of 43 Wnt genes and abnormal expression of 13 Wnt genes occurred at a high frequency in GC tumors, and gene amplification and deletion are the major mutation types. Clusters of DNA methylation associated with Wnt signaling genes and GC tumors were also revealed, and a significant increase in β-catenin activity was found in the hypermethylated group of GC tumors. In addition, overexpression of DKK2 gene significantly inhibited multiple biological processes of the GC cells, including their growth, clonal forming, migration, and invasion ability, and induced apoptosis of the GC cells. CONCLUSIONS: Our current study suggested that gene mutation, abnormal gene expression, and altered DNA methylation profiles associated with the Wnt signaling may play an important role in gastric carcinogenesis, and DKK2 gene may act as a tumor suppressor in gastric cells.
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