Expression of esophageal cancer related gene 4 (ECRG4), a novel tumor suppressor gene, in esophageal cancer and its inhibitory effect on the tumor growth in vitro and in vivo

Authors

  • Lin-Wei Li,

    1. State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
    Current affiliation:
    1. Department of Oncology, Henan Provincial People's Hospital, Zheng-Zhou, People's Republic of China
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  • Xi-Ying Yu,

    1. State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
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  • Yang Yang,

    1. State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
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  • Chun-Peng Zhang,

    1. State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
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  • Li-Ping Guo,

    1. State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
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  • Shih-Hsin Lu

    Corresponding author
    1. State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
    • State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100-021, People's Republic of China
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    • Fax: +86-10-6771-2368.


Abstract

The ECRG4 gene was initially identified and cloned in our laboratory from human normal esophageal epithelium (GenBank accession no. AF325503). We revealed the expression of ECRG4 protein was downregulated in 68.5% (89/130) ESCC samples using tissue microarray. The low ECRG4 protein expression was significantly associated with regional lymph node metastasis, primary tumor size, and tumor stage in ESCC (p < 0.05). ECRG4 mRNA expression was downregulated in ESCC due to the hypermethylation in the gene promoter. The treatment with 5-aza-2′-deoxycytidine, which is a DNA methyltransferase inhibitor restored ECRG4 mRNA expression in ESCC cells. The result indicated that promoter hypermethylation may be 1 main mechanism leading to the silencing of ECRG4. The high expression of ECRG4 in patients with ESCC was associated with longer survival compared with those with low ECRG4 expression by Kaplan-Meier survival analysis (p < 0.05). ECRG4 protein was an independent prognostic factor for ESCC by multivariable Cox proportional hazards regression analysis (p < 0.05). The restoration of ECRG4 expression in ESCC cells inhibited cell proliferation, colony formation, anchorage-independent growth, cell cycle progression and tumor growth in vivo (p < 0.05). The transfection of ECRG4 gene in ESCC cells inhibited the expression of NF-κB and nuclear translocation, in addition to the expression of COX-2, a NF-κB target gene, was attenuated. Taken together, ECRG4 is a novel candidate tumor suppressor gene in ESCC, and ECRG4 protein is a candidate prognostic marker for ESCC. © 2009 UICC

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