eIF4EBP3 was downregulated by methylation and acted as a tumor suppressor by targeting eIF4E/β-catenin in gastric cancer.

Abstract

BACKGROUND:

Epigenetic aberrations of tumor suppressor genes (TSGs), particularly DNA methylation, are frequently involved in the pathogenesis of gastric cancer (GC). Through a methylome study, we identified eIF4EBP3 as a methylated gene in GC. However, the role of eIF4EBP3 in GC progression has not been explored.

METHODS:

The expression and promoter region methylation of eIF4EBP3 in GC and healthy tissues were analyzed in public datasets. eIF4EBP3 expression in GC was detected by semi-quantitative RT-PCR, western blot and immunohistochemistry. We also studied epigenetic alterations and functions in GC. The effects of eIF4EBP3 on cell proliferation, migration and invasion were conducted by functional experiments in vitro and in vivo. Label-free proteomic analysis was applied to identify targets of eIF4EBP3.

RESULTS:

The expression level of eIF4EBP3 was downregulated in gastric cancer due to promoter region methylation, and was associated with poor survival and tumor progression. Ectopic expression of eIF4EBP3 significantly inhibited tumor cell growth, migration and invasion both in vitro and in vivo. Label-free proteomic analysis indicated eIF4EBP3 downregulated the protein level of β-catenin, which was confirmed by western blot. Overexpression of β-catenin reversed the inhibitory effects of eIF4EBP3 on cell growth and migration, indicating that eIF4EBP3 acts on GC cells by targeting the eIF4E/β-catenin axis.

CONCLUSION:

These results suggest that eIF4EBP3 is a novel TSG methylated in gastric cancer that may play important roles in GC development and liver metastasis and indicate eIF4EBP3 as a potential metastasis and survival biomarker for GC.

• Authors: Shuting Zhai, Shuang Lin, Zhongjie Lin, Junjie Xu, Tong Ji, Ke Chen, Ke Wu, Hui Liu, Hanning Ying, Weiqiang Fei, Jin Wang, Guoxiang Fu, Yifan Wang, Xiaotong Hu, Xiujun Cai
• Journal: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association (Gastric Cancer) Vol. 23 Issue 3 Pg. 483-496 (05 2020) ISSN: 1436-3305 [Electronic] Japan
• PMID: 31853750 (Publication Type: Journal Article)

Chemical References

• Biomarkers, Tumor
• CTNNB1 protein, human
• Carrier Proteins
• EIF4E protein, human
• EIF4EBP3 protein, human
• Eukaryotic Initiation Factor-4E
• beta Catenin

Topics

• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Carrier Proteins (genetics, metabolism)
• Cell Movement
• Cell Proliferation
• DNA Methylation
• Eukaryotic Initiation Factor-4E (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Humans
• Male
• Mice
• Mice, Nude
• Prognosis
• Promoter Regions, Genetic
• Stomach Neoplasms (genetics, metabolism, pathology)
• Survival Rate
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• beta Catenin (genetics, metabolism)