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Comprehensive Analysis of the Canonical and Non-canonical Wnt Signaling Pathways in Gastric Cancer

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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.

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Funding

This study was funded by the National Natural Science Foundation of China (Grant No. 81760441).

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Author notes

  1. Le Wang and Hao Wang are co-first authors and have contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an, China

    Le Wang

  2. National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, No. 229 North Taibai Road, Xi’an, 710000, China

    Le Wang, Hao Wang & Penggao Dai

  3. The Second Department of General Surgery, Shaanxi Provincial People’s Hospital, Xi’an, China

    Xianglong Duan

  4. Department of General Surgery, The First Hospital of Yulin, Shaanxi, China

    Xianglong Duan

  5. Department of Otolaryngology, Xi’an No.4 Hospital, No. 21 Jiefang Road, Xi’an, 710004, Shaanxi, China

    Jianping Li

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  1. Le Wang
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  4. Penggao Dai
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Correspondence to Penggao Dai or Jianping Li.

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Wang, L., Wang, H., Duan, X. et al. Comprehensive Analysis of the Canonical and Non-canonical Wnt Signaling Pathways in Gastric Cancer. Dig Dis Sci 64, 2830–2842 (2019). https://doi.org/10.1007/s10620-019-05606-6

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  • DOI: https://doi.org/10.1007/s10620-019-05606-6

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