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食管癌中涉及SEI1/SET/NM23H1途径的基因组不稳定性新机制的特征 |
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Characterization of a novel mechanism of genomic instability involving the SEI1/SET/NM23H1 pathway in esophageal cancers |
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Li Y, Nie C-J, Hu L, Qin Y, Liu H-B, Zeng T-T, Chen L, Fu L, Deng W, Chen S-P, Jia W-H, Zhang C, Xie D, Guan X-Y 2010/8/19 16:30:00 |
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Cancer Research, 2010, Volume 70, Issue 14
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Amplification of 19q is a frequent genetic alteration in many solid tumors, and SEI1 is a candidate oncogene within the amplified region. Our previous study found that the oncogenic function of SEI1 was associated with chromosome instability. In this study, we report a novel mechanism of genomic instability involving the SEI1-SET-NM23H1 pathway. Overexpression of SEI1 was observed in 57 of 100 of esophageal squamous cell carcinoma cases. Functional study showed that SEI1 had strong tumorigenic ability, and overexpression of SEI1 could induce the genomic instability by increasing micronuclei formation and reducing the number of chromosomes. Further study found that SEI1 was able to upregulate SET expression and subsequently promote the translocation of a small amount of NM23H1 from the cytoplasm to the nucleus. Nuclear NM23H1 can induce DNA damage through its DNA nick activity. Unlike CTL attack, only a small amount of NM23H1 translocated into the nucleus (<10%) induced by the overexpression of SEI1. Further study found that the small amount of NM23H1 only induced minor DNA damage and subsequently increased genomic instability, rather than inducing irreparable DNA damage and initiating apoptosis by CTL attack. Sister chromatid exchange experiment found that the translocation of small amount of NM23H1 into the nucleus induced by the overexpressions of SEI1/SET could increase the frequency of sister chromatid exchange. In addition, overexpression of SEI1 was associated with poor prognosis of esophageal squamous cell carcinoma. Taken together, these findings define a novel mechanism of genomic instability and malignant progression in esophageal cancers, a deadly disease of increasing incidence in developed countries. ©2010 AACR.
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Correspondence Address: Guan, X.-Y.; University of Hong Kong, LKS Faculty of Medicine Building, HKU, 21 Sassoon Road, Pokfulam, Hong Kong; email:xyguan@hkucc.hku.hk |
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疾病资源中心
王燕燕 王曙
上海交通大学附属瑞金医院内分泌科
患者,女,69岁。2009年1月无明显诱因下出现乏力,当时程度较轻,未予以重视。2009年3月患者乏力症状加重,尿色逐渐加深,大便习惯改变,颜色变淡。4月18日入我院感染科治疗,诉轻度头晕、心慌,体重减轻10kg。无肝区疼痛,无发热,无腹痛、腹泻、腹胀、里急后重,无恶性、呕吐等。入院半月前于外院就诊,查肝功能:ALT 601IU/L,AST 785IU/L,TBIL 97.7umol/L,白蛋白 41g/L,甲状腺功能:游离T3 30.6pmol/L,游离T4 51.9pmol/L,心电图示快速房颤。
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