Shuting Zhai1, Shuang Lin2, Zhongjie Lin1, Junjie Xu1, Tong Ji1, Ke Chen1, Ke Wu1, Hui Liu1, Hanning Ying1, Weiqiang Fei3, Jin Wang3, Guoxiang Fu3, Yifan Wang4, Xiaotong Hu5, Xiujun Cai6. 1. Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China. 2. Department of Lung Transplantation, Department of Thoracic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China. 3. Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China. 4. Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China. anwyf@zju.edu.cn. 5. Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, Zhejiang, China. hxt_hz@zju.edu.cn. 6. Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China. srrsh_cxj@zju.edu.cn.
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.
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: Zhao-Qiu Wu; Xiao-Yan Li; Casey Yuexian Hu; Michael Ford; Celina G Kleer; Stephen J Weiss Journal: Proc Natl Acad Sci U S A Date: 2012-09-24 Impact factor: 11.205
Authors: Qian Tao; He Huang; Theresa M Geiman; Chai Yen Lim; Li Fu; Guo-Hua Qiu; Keith D Robertson Journal: Hum Mol Genet Date: 2002-09-01 Impact factor: 6.150
Authors: Jordi Barretina; Giordano Caponigro; Nicolas Stransky; Kavitha Venkatesan; Adam A Margolin; Sungjoon Kim; Christopher J Wilson; Joseph Lehár; Gregory V Kryukov; Dmitriy Sonkin; Anupama Reddy; Manway Liu; Lauren Murray; Michael F Berger; John E Monahan; Paula Morais; Jodi Meltzer; Adam Korejwa; Judit Jané-Valbuena; Felipa A Mapa; Joseph Thibault; Eva Bric-Furlong; Pichai Raman; Aaron Shipway; Ingo H Engels; Jill Cheng; Guoying K Yu; Jianjun Yu; Peter Aspesi; Melanie de Silva; Kalpana Jagtap; Michael D Jones; Li Wang; Charles Hatton; Emanuele Palescandolo; Supriya Gupta; Scott Mahan; Carrie Sougnez; Robert C Onofrio; Ted Liefeld; Laura MacConaill; Wendy Winckler; Michael Reich; Nanxin Li; Jill P Mesirov; Stacey B Gabriel; Gad Getz; Kristin Ardlie; Vivien Chan; Vic E Myer; Barbara L Weber; Jeff Porter; Markus Warmuth; Peter Finan; Jennifer L Harris; Matthew Meyerson; Todd R Golub; Michael P Morrissey; William R Sellers; Robert Schlegel; Levi A Garraway Journal: Nature Date: 2012-03-28 Impact factor: 49.962