ZNRD1在食管癌及EC109细胞中的表达及其临床意义研究
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摘要
背景
食管癌是目前对人类健康和生命构成严重威胁的恶性肿瘤之一,在各种恶性肿瘤导致的死亡中食管癌占第六位,在我国一些高发地区居于各种恶性肿瘤的首位。食管癌预后较差,主要原因是肿瘤在早期即可发生外侵或转移。食管癌的发生发展是多基因共同作用的后果。目前在食管癌组织中已发现多种表达异常的基因和蛋白,但具有临床应用价值的分子标志物却甚少,能够对食管癌患者治疗效果和预后判断提供可靠依据的标志物尚需进一步研究证实和寻找。锌带蛋白基因1(Zinc ribbon domain-containing 1,ZNRD1)是一种与转录相关的锌带蛋白,可能通过调节转录起始位点的选择、RNA合成的延长和终止在转录中发挥重要调控作用。ZNRD1的表达可以抑制胃癌细胞系在体内外的生长和致瘤性,并且能够抑制胃癌细胞系体外转化表型,进而逆转一些胃癌细胞系在体内外的恶性生长潜能,表明ZNRD1在肿瘤发展中能发挥一定的抑制作用,有可能是潜在的肿瘤基因治疗靶点。ZNRD1在食管癌细胞内的作用、其抗凋亡的机制、与食管癌发生有无关系等均未见报道。本研究一方面旨在探讨ZNRD1在食管癌组织中的差异表达,了解ZNRD1表达水平与患者临床病理特征和预后之间的关系;另外,以ZNRD1真核正义表达载体转染人源性食管鳞癌细胞系EC109,构建ZNRD1基因高表达的食管鳞癌细胞亚系,探讨ZNRD1过表达对EC109细胞增殖、凋亡、转移以及DNA损伤修复等生物学行为的影响和作用机制,为深入理解ZNRD1在食管癌中的作用奠定理论基础。研究结果可望为食管癌的基因治疗和预后判断提供具有一定临床应用价值的选择。
目的
研究ZNRD1基因在食管癌组织及其对应近癌、远癌组织中的表达情况,了解ZNRD1表达水平与患者临床病理特征和预后之间的关系,为ZNRD1作为食管癌预后判断候选基因提供实验依据;检测食管鳞癌细胞系EC109中ZNRD1表达水平,构建ZNRD1表达上调的食管鳞癌细胞亚系,研究ZNRD1表达对食管鳞癌细胞系EC109增殖、凋亡以及转移等生物学行为的影响和作用机制;探讨ZNRD1表达水平对EC109细胞化疗药物敏感性及DNA损伤修复功能的影响及其可能的分子机制。
方法
(1)应用逆转录聚合酶链反应(RT-PCR)和免疫组织化学(IHC)技术检测食管癌患者肿瘤组织及其对应近癌、远癌组织中ZNRD1基因的表达;
(2)采用IHC技术检测食管癌患者肿瘤组织中ZNRD1蛋白的表达,结合随访资料进行统计分析;
(3)应用RT-PCR、Western blot和免疫细胞化学(ICC)技术检测ZNRD1基因在食管鳞癌细胞系EC109中的表达;
(4)利用脂质体转染法建立ZNRD1基因过表达的食管鳞癌细胞模型,并利用RT-PCR和Western blot技术进行鉴定;
(5)利用MTT实验绘制转染细胞、对照细胞及亲本细胞的生长曲线;
(6)通过Transwell侵袭小室实验检测ZNRD1过表达对食管鳞癌细胞侵袭活性的影响;
(7)通过流式细胞仪分析转染细胞及对照细胞的细胞周期和细胞凋亡的变化;
(8)通过MTT实验进行体外药物敏感性分析,计算细胞对药物的IC50值;
(9)通过流式细胞仪和DNA断裂实验检测ZNRD1过表达对EC109细胞凋亡敏感性的影响;
(10)利用单细胞凝胶电泳(SCGE)技术检测紫外线(UV)照射对转染细胞及其对照细胞的DNA损伤修复效应;
(11)通过基因芯片检测ZNRD1过表达对EC109细胞基因表达谱的影响;
(12)利用RT-PCR和Western blot对基因芯片的结果进行鉴定。
结果
(1) ZNRD1在食管癌组织中的表达水平明显低于近癌及远癌组织;ZNRD1在食管癌患者肿瘤组织及其对应近癌、远癌组织中的表达率分别为29.5%、52.3%和72.7%,ZNRD1在近癌及远癌组织中的表达率显著高于肿瘤组织(p < 0.05);
(2)转染细胞经RT-PCR和Western blot证实,成功建立了ZNRD1过表达的食管鳞癌细胞模型;
(4) MTT实验及集落形成实验结果表明,上调ZNRD1可以导致食管鳞癌细胞系EC109生长及增殖速度减慢;
(5) Transwell侵袭小室实验结果显示,上调ZNRD1可以显著降低食管鳞癌细胞系EC109的侵袭活性;
(6)流式细胞仪检测结果表明,上调ZNRD1可以导致EC109细胞出现G1期阻滞,S期比例减少;
(7)体外药物敏感实验结果表明,上调ZNRD1能够显著降低EC109细胞对5-氟尿嘧啶(5-Fu)、顺铂(CDDP)、长春新碱(VCR)和阿霉素(ADR)的敏感性,增强EC109细胞对化疗药物的耐受性;
(8)流式细胞仪检测及DNA断裂实验结果表明,上调ZNRD1可以降低EC109细胞对阿霉素的敏感性,增加食管鳞癌细胞株EC109的抗凋亡能力;
(9) SCGE实验结果表明,上调ZNRD1表达水平能够显著增强EC109细胞的DNA修复能力,抑制紫外线照射对食管鳞癌细胞EC109的DNA损伤效应;
(10)基因芯片检测结果表明,上调ZNRD1可能改变61种基因的表达水平;
(11)经RT-PCR和Western blot证实,转染ZNRD1可以显著上调ERCC1、P-gp、Bcl-2、和MDR1等基因的表达。
结论
ZNRD1在食管癌组织中的表达水平显著低于对应近癌及远癌组织;ZNRD1表达水平与患者预后呈正相关:肿瘤组织中ZNRD1表达水平高者其预后明显优于ZNRD1低表达患者。食管鳞癌细胞系EC109中ZNRD1 mRNA及蛋白表达均为阴性,上调ZNRD1可以在一定程度上逆转食管鳞癌细胞系EC109的恶性表型,导致EC109细胞生长和增殖速度明显减慢,细胞出现G1期阻滞,抑制EC109细胞的侵袭活性,ZNRD1可能通过调节CDKN1A等基因表达参与细胞周期调控。上调ZNRD1可以降低EC109细胞的药物敏感性,抑制EC109细胞凋亡。ZNRD1可能通过调节DNA损伤修复相关基因ERCC1及Bcl-2的表达水平进而参与紫外线及铂类化疗药物等DNA损伤因子对EC109细胞的DNA损伤效应。
Background
Esophageal cancer is one of the most prevalent and deadliest malignancies. Worldwide, esophageal cancer is the sixth leading cause of death from cancer, and even the most frequent malignant tumor in several regions of China. Due to metastasis and invasion of surrounding tissues in early stage, the prognosis of esophageal cancer still remains poor. Numerous genes involve in the pathogenesis of esophageal cancer, but the concrete process remains unclear. Multiple genes and proteins with abnormal expression have been found in esophageal cancer. However, a few of them can be adopted as biomarkers with clinical value. The other biomarkers related to evaluating therapeutic efficacy and prognosis need further searching and confirming. As a zinc band protein related to transcription, the ZNRD1 (Zinc ribbon domain-containing 1) gene might play important role in the process of transcription through regulating the choice of transcriptional start site, as well as the extension and termination for synthesis of RNA. Overexpression of ZNRD1 can suppress the proliferation and oncogenicity of stomach cancer cells in vitro and in vivo, and restrain its transform phenotype, thus reversing the malignant proliferation potency of some stomach cancer cells. These fingings suggest that ZNRD1 gene transduction may be a useful new strategy of gene therapy for gastric cancer. However, there is still no report about the role of ZNRD1 in esophageal cancer cells, and the precise mechanism of apoptosis regulation by ZNRD1, as well as the clinical value of ZNRD1 in evaluating therapeutic efficacy and prognosis. In this study, we explored the differential expression of ZNRD1 in esophageal cancer tissues; to understanded the relation between the level of ZNRD1 expression and clinical pathological features, as well as the prognosis of patients underwent radical esophagectomy. In addition, we transfected the eukaryotic sence expression vector of ZNRD1 into EC109 cells, and also explored the function and possible mechanisms of ZNRD1 related biological behaviours, such as proliferation, apoptosis, metastasis, as well as DNA damage and repair. All these laid a solid basis for the role of ZNRD1 in esophageal cancer.
Aims: To identify the differential expression of ZNRD1 in esophageal cancer tissues and investigate the relationship between the expression of ZNRD1 and the prognosis of patients with esophageal cancer. In addition, the correlation between ZNRD1 expression and the clinical pathological characteristics was also investigated. For exploring the function and possible mechanisms of ZNRD1 related biological behaviours, such as proliferation, apoptosis, metastasis, as well as DNA damage and repair, the eukaryotic sence expression vector of ZNRD1 was transfected into EC109 cells.
Methods: (1) Semiquantitative RT-PCR assay and immunohistochemistry staining technique were used to identify the differential expression of ZNRD1 mRNA and protein in esophageal cancer, normal and adjacent tissues.
(2) The relationship between ZNRD1 expression and prognosis of patients with esophageal cancer was investigated by immunohistochemistry staining technique and statistical analysis.
(3) The Western blot, RT-PCR assay and immunocytochemistry staining were used to detect the ZNRD1 expression in EC109 cells.
(4) The eukaryotic sence expression vector of ZNRD1 was transfected into EC109 cells by liposome transfection technique, and then Western blot, RT-PCR assay and immunocytochemistry staining were used to detect the expression of ZNRD1.
(5) Growth curve and drug sensitivity assay were performed using MTT assay. IC50 values of EC109 cells to anticancer drugs were calculated.
(6) Invasion activity of transfected EC109 cells was investigated by Transwell loculus assay.
(7) Cell cycle analysis was performed using flow cytometry.
(8) The apoptosis sensitivity of transfectant and control cells was detected by DNA fragmentation assay and flow cytometry.
(9) Utilizing single cell gel electrophoresis (SCGE) assay to evaluate the DNA damage and repair induced by ultraviolet light radiation.
(10) The cDNA microarray analysis was performed to identify the gene expression profile mediated by ZNRD1 overexpression.
(11) RT-PCR and Western blots were performed to validate the differential expression of genes identified by cDNA microarray analysis.
Results: (1) the ZNRD1 expression was confirmed to be down-regulated in esophageal cancer tissues compared to normal and adjacent nonneoplastic tissues. As immunohistochemistry discovered, the positive expressing rate of ZNRD1 in esophageal cancer (29.5%) was lower than in adjacent nonneoplastic (52.3%) and normal tissues (72.7%) (p < 0.05).
(2) The mRNA and protein levels of ZNRD1 were both undetectable in EC109 cells, while significantly higher expression of ZNRD1 mRNA and protein (p < 0.01) was observed in EC109/ZNRD1 cells. The results showed that ZNRD1 gene was successfully transfected into and expressed in the EC109 cells.
(3) MTT and colony formation assay showed that upregulation of ZNRD1 could suppress cell growth and proliferation of EC109 cells.
(4) As Transwell loculus assay showed, the invasion activity of EC109 cells was significantly suppressed by the overexpression of ZNRD1.
(5) As showed by flow cytometry, ZNRD1 upregulated esophageal cancer cells EC109/ZNRD1 exhibited G1 stage blockage and less percentage of cells in S stage.
(6) MTT assay showed that transfectant cell was more resistant to 5-Fu, CDDP, VCR and ADR than control cells.
(7) According to the results of flow cytometry and DNA fragmentation assay, the apoptosis sensitivity of EC109/ZNRD1 was lower than control cells.
(8) ZNRD1-expressing cells exhibited a significant enhanced DNA repair capacity, suggesting that upregulation of ZNRD1 could inhibit the DNA damage induced by ultraviolet light radiation.
(9) As the cDNA microarray analysis discovered, there were 61 genes with different expression levels following the upregulation of ZNRD1 in EC109 cells.
(10) Western blot showed that the overexpression of ZNRD1 can effectively upregulate the mRNA level of ERCC1, P-gp, MDR1 and Bcl-2 in EC109/ZNRD1, as compared with the control cells.
Conclusions: ZNRD1 expression was confirmed to be down-regulated in esophageal cancer tissues compared to normal and adjacent nonneoplastic tissues by RT-PCR and immunohistochemistry. The expression of ZNRD1 in esophageal cancer was positive correlated to the prognosis of patients. The decreased expression of ZNRD1 was correlated with a worse outcome of patients with esophageal cancer. The mRNA and protein levels of ZNRD1 were both undetectable in EC109 cells, while significantly higher expression of ZNRD1 mRNA and protein was observed in EC109/ZNRD1 cells, which suggested that ZNRD1 gene was successfully transfected into and expressed in the EC109 cells. Upregulation of the ZNRD1 could partly reverse the malignant phenotype of EC109 cells, resulting in the suppressed cell growth, G1 stage blockage and the inhibited invasion activity. ZNRD1 might regulate the cell cycle by altering the expression of CDKN1A (Cyclin-dependent kinase inhibitor 1A). Moreover, upregulation of ZNRD1 could enhance the resistance of EC109 cells to chemotherapeutics and suppress the apoptosis. ZNRD1-expressing EC109 cells exhibited a significant enhanced DNA repair capacity, and the overexpression of ZNRD1 could upregulate the expression of excision repair cross-complementing 1 (ERCC1) gene. Thus suggested ZNRD1 might play an important role in the process of DNA damage and repair by regulating the expression of ERCC1. In addition, the ZNRD1 gene might be involved in the cisplatin resistance of EC109 cells by regulating the expression of ERCC1 and Bcl-2.
食管癌是目前对人类健康和生命构成严重威胁的恶性肿瘤之一,在各种恶性肿瘤导致的死亡中食管癌占第六位,在我国一些高发地区居于各种恶性肿瘤的首位。食管癌预后较差,主要原因是肿瘤在早期即可发生外侵或转移。食管癌的发生发展是多基因共同作用的后果。目前在食管癌组织中已发现多种表达异常的基因和蛋白,但具有临床应用价值的分子标志物却甚少,能够对食管癌患者治疗效果和预后判断提供可靠依据的标志物尚需进一步研究证实和寻找。锌带蛋白基因1(Zinc ribbon domain-containing 1,ZNRD1)是一种与转录相关的锌带蛋白,可能通过调节转录起始位点的选择、RNA合成的延长和终止在转录中发挥重要调控作用。ZNRD1的表达可以抑制胃癌细胞系在体内外的生长和致瘤性,并且能够抑制胃癌细胞系体外转化表型,进而逆转一些胃癌细胞系在体内外的恶性生长潜能,表明ZNRD1在肿瘤发展中能发挥一定的抑制作用,有可能是潜在的肿瘤基因治疗靶点。ZNRD1在食管癌细胞内的作用、其抗凋亡的机制、与食管癌发生有无关系等均未见报道。本研究一方面旨在探讨ZNRD1在食管癌组织中的差异表达,了解ZNRD1表达水平与患者临床病理特征和预后之间的关系;另外,以ZNRD1真核正义表达载体转染人源性食管鳞癌细胞系EC109,构建ZNRD1基因高表达的食管鳞癌细胞亚系,探讨ZNRD1过表达对EC109细胞增殖、凋亡、转移以及DNA损伤修复等生物学行为的影响和作用机制,为深入理解ZNRD1在食管癌中的作用奠定理论基础。研究结果可望为食管癌的基因治疗和预后判断提供具有一定临床应用价值的选择。
目的
研究ZNRD1基因在食管癌组织及其对应近癌、远癌组织中的表达情况,了解ZNRD1表达水平与患者临床病理特征和预后之间的关系,为ZNRD1作为食管癌预后判断候选基因提供实验依据;检测食管鳞癌细胞系EC109中ZNRD1表达水平,构建ZNRD1表达上调的食管鳞癌细胞亚系,研究ZNRD1表达对食管鳞癌细胞系EC109增殖、凋亡以及转移等生物学行为的影响和作用机制;探讨ZNRD1表达水平对EC109细胞化疗药物敏感性及DNA损伤修复功能的影响及其可能的分子机制。
方法
(1)应用逆转录聚合酶链反应(RT-PCR)和免疫组织化学(IHC)技术检测食管癌患者肿瘤组织及其对应近癌、远癌组织中ZNRD1基因的表达;
(2)采用IHC技术检测食管癌患者肿瘤组织中ZNRD1蛋白的表达,结合随访资料进行统计分析;
(3)应用RT-PCR、Western blot和免疫细胞化学(ICC)技术检测ZNRD1基因在食管鳞癌细胞系EC109中的表达;
(4)利用脂质体转染法建立ZNRD1基因过表达的食管鳞癌细胞模型,并利用RT-PCR和Western blot技术进行鉴定;
(5)利用MTT实验绘制转染细胞、对照细胞及亲本细胞的生长曲线;
(6)通过Transwell侵袭小室实验检测ZNRD1过表达对食管鳞癌细胞侵袭活性的影响;
(7)通过流式细胞仪分析转染细胞及对照细胞的细胞周期和细胞凋亡的变化;
(8)通过MTT实验进行体外药物敏感性分析,计算细胞对药物的IC50值;
(9)通过流式细胞仪和DNA断裂实验检测ZNRD1过表达对EC109细胞凋亡敏感性的影响;
(10)利用单细胞凝胶电泳(SCGE)技术检测紫外线(UV)照射对转染细胞及其对照细胞的DNA损伤修复效应;
(11)通过基因芯片检测ZNRD1过表达对EC109细胞基因表达谱的影响;
(12)利用RT-PCR和Western blot对基因芯片的结果进行鉴定。
结果
(1) ZNRD1在食管癌组织中的表达水平明显低于近癌及远癌组织;ZNRD1在食管癌患者肿瘤组织及其对应近癌、远癌组织中的表达率分别为29.5%、52.3%和72.7%,ZNRD1在近癌及远癌组织中的表达率显著高于肿瘤组织(p < 0.05);
(2)转染细胞经RT-PCR和Western blot证实,成功建立了ZNRD1过表达的食管鳞癌细胞模型;
(4) MTT实验及集落形成实验结果表明,上调ZNRD1可以导致食管鳞癌细胞系EC109生长及增殖速度减慢;
(5) Transwell侵袭小室实验结果显示,上调ZNRD1可以显著降低食管鳞癌细胞系EC109的侵袭活性;
(6)流式细胞仪检测结果表明,上调ZNRD1可以导致EC109细胞出现G1期阻滞,S期比例减少;
(7)体外药物敏感实验结果表明,上调ZNRD1能够显著降低EC109细胞对5-氟尿嘧啶(5-Fu)、顺铂(CDDP)、长春新碱(VCR)和阿霉素(ADR)的敏感性,增强EC109细胞对化疗药物的耐受性;
(8)流式细胞仪检测及DNA断裂实验结果表明,上调ZNRD1可以降低EC109细胞对阿霉素的敏感性,增加食管鳞癌细胞株EC109的抗凋亡能力;
(9) SCGE实验结果表明,上调ZNRD1表达水平能够显著增强EC109细胞的DNA修复能力,抑制紫外线照射对食管鳞癌细胞EC109的DNA损伤效应;
(10)基因芯片检测结果表明,上调ZNRD1可能改变61种基因的表达水平;
(11)经RT-PCR和Western blot证实,转染ZNRD1可以显著上调ERCC1、P-gp、Bcl-2、和MDR1等基因的表达。
结论
ZNRD1在食管癌组织中的表达水平显著低于对应近癌及远癌组织;ZNRD1表达水平与患者预后呈正相关:肿瘤组织中ZNRD1表达水平高者其预后明显优于ZNRD1低表达患者。食管鳞癌细胞系EC109中ZNRD1 mRNA及蛋白表达均为阴性,上调ZNRD1可以在一定程度上逆转食管鳞癌细胞系EC109的恶性表型,导致EC109细胞生长和增殖速度明显减慢,细胞出现G1期阻滞,抑制EC109细胞的侵袭活性,ZNRD1可能通过调节CDKN1A等基因表达参与细胞周期调控。上调ZNRD1可以降低EC109细胞的药物敏感性,抑制EC109细胞凋亡。ZNRD1可能通过调节DNA损伤修复相关基因ERCC1及Bcl-2的表达水平进而参与紫外线及铂类化疗药物等DNA损伤因子对EC109细胞的DNA损伤效应。
Background
Esophageal cancer is one of the most prevalent and deadliest malignancies. Worldwide, esophageal cancer is the sixth leading cause of death from cancer, and even the most frequent malignant tumor in several regions of China. Due to metastasis and invasion of surrounding tissues in early stage, the prognosis of esophageal cancer still remains poor. Numerous genes involve in the pathogenesis of esophageal cancer, but the concrete process remains unclear. Multiple genes and proteins with abnormal expression have been found in esophageal cancer. However, a few of them can be adopted as biomarkers with clinical value. The other biomarkers related to evaluating therapeutic efficacy and prognosis need further searching and confirming. As a zinc band protein related to transcription, the ZNRD1 (Zinc ribbon domain-containing 1) gene might play important role in the process of transcription through regulating the choice of transcriptional start site, as well as the extension and termination for synthesis of RNA. Overexpression of ZNRD1 can suppress the proliferation and oncogenicity of stomach cancer cells in vitro and in vivo, and restrain its transform phenotype, thus reversing the malignant proliferation potency of some stomach cancer cells. These fingings suggest that ZNRD1 gene transduction may be a useful new strategy of gene therapy for gastric cancer. However, there is still no report about the role of ZNRD1 in esophageal cancer cells, and the precise mechanism of apoptosis regulation by ZNRD1, as well as the clinical value of ZNRD1 in evaluating therapeutic efficacy and prognosis. In this study, we explored the differential expression of ZNRD1 in esophageal cancer tissues; to understanded the relation between the level of ZNRD1 expression and clinical pathological features, as well as the prognosis of patients underwent radical esophagectomy. In addition, we transfected the eukaryotic sence expression vector of ZNRD1 into EC109 cells, and also explored the function and possible mechanisms of ZNRD1 related biological behaviours, such as proliferation, apoptosis, metastasis, as well as DNA damage and repair. All these laid a solid basis for the role of ZNRD1 in esophageal cancer.
Aims: To identify the differential expression of ZNRD1 in esophageal cancer tissues and investigate the relationship between the expression of ZNRD1 and the prognosis of patients with esophageal cancer. In addition, the correlation between ZNRD1 expression and the clinical pathological characteristics was also investigated. For exploring the function and possible mechanisms of ZNRD1 related biological behaviours, such as proliferation, apoptosis, metastasis, as well as DNA damage and repair, the eukaryotic sence expression vector of ZNRD1 was transfected into EC109 cells.
Methods: (1) Semiquantitative RT-PCR assay and immunohistochemistry staining technique were used to identify the differential expression of ZNRD1 mRNA and protein in esophageal cancer, normal and adjacent tissues.
(2) The relationship between ZNRD1 expression and prognosis of patients with esophageal cancer was investigated by immunohistochemistry staining technique and statistical analysis.
(3) The Western blot, RT-PCR assay and immunocytochemistry staining were used to detect the ZNRD1 expression in EC109 cells.
(4) The eukaryotic sence expression vector of ZNRD1 was transfected into EC109 cells by liposome transfection technique, and then Western blot, RT-PCR assay and immunocytochemistry staining were used to detect the expression of ZNRD1.
(5) Growth curve and drug sensitivity assay were performed using MTT assay. IC50 values of EC109 cells to anticancer drugs were calculated.
(6) Invasion activity of transfected EC109 cells was investigated by Transwell loculus assay.
(7) Cell cycle analysis was performed using flow cytometry.
(8) The apoptosis sensitivity of transfectant and control cells was detected by DNA fragmentation assay and flow cytometry.
(9) Utilizing single cell gel electrophoresis (SCGE) assay to evaluate the DNA damage and repair induced by ultraviolet light radiation.
(10) The cDNA microarray analysis was performed to identify the gene expression profile mediated by ZNRD1 overexpression.
(11) RT-PCR and Western blots were performed to validate the differential expression of genes identified by cDNA microarray analysis.
Results: (1) the ZNRD1 expression was confirmed to be down-regulated in esophageal cancer tissues compared to normal and adjacent nonneoplastic tissues. As immunohistochemistry discovered, the positive expressing rate of ZNRD1 in esophageal cancer (29.5%) was lower than in adjacent nonneoplastic (52.3%) and normal tissues (72.7%) (p < 0.05).
(2) The mRNA and protein levels of ZNRD1 were both undetectable in EC109 cells, while significantly higher expression of ZNRD1 mRNA and protein (p < 0.01) was observed in EC109/ZNRD1 cells. The results showed that ZNRD1 gene was successfully transfected into and expressed in the EC109 cells.
(3) MTT and colony formation assay showed that upregulation of ZNRD1 could suppress cell growth and proliferation of EC109 cells.
(4) As Transwell loculus assay showed, the invasion activity of EC109 cells was significantly suppressed by the overexpression of ZNRD1.
(5) As showed by flow cytometry, ZNRD1 upregulated esophageal cancer cells EC109/ZNRD1 exhibited G1 stage blockage and less percentage of cells in S stage.
(6) MTT assay showed that transfectant cell was more resistant to 5-Fu, CDDP, VCR and ADR than control cells.
(7) According to the results of flow cytometry and DNA fragmentation assay, the apoptosis sensitivity of EC109/ZNRD1 was lower than control cells.
(8) ZNRD1-expressing cells exhibited a significant enhanced DNA repair capacity, suggesting that upregulation of ZNRD1 could inhibit the DNA damage induced by ultraviolet light radiation.
(9) As the cDNA microarray analysis discovered, there were 61 genes with different expression levels following the upregulation of ZNRD1 in EC109 cells.
(10) Western blot showed that the overexpression of ZNRD1 can effectively upregulate the mRNA level of ERCC1, P-gp, MDR1 and Bcl-2 in EC109/ZNRD1, as compared with the control cells.
Conclusions: ZNRD1 expression was confirmed to be down-regulated in esophageal cancer tissues compared to normal and adjacent nonneoplastic tissues by RT-PCR and immunohistochemistry. The expression of ZNRD1 in esophageal cancer was positive correlated to the prognosis of patients. The decreased expression of ZNRD1 was correlated with a worse outcome of patients with esophageal cancer. The mRNA and protein levels of ZNRD1 were both undetectable in EC109 cells, while significantly higher expression of ZNRD1 mRNA and protein was observed in EC109/ZNRD1 cells, which suggested that ZNRD1 gene was successfully transfected into and expressed in the EC109 cells. Upregulation of the ZNRD1 could partly reverse the malignant phenotype of EC109 cells, resulting in the suppressed cell growth, G1 stage blockage and the inhibited invasion activity. ZNRD1 might regulate the cell cycle by altering the expression of CDKN1A (Cyclin-dependent kinase inhibitor 1A). Moreover, upregulation of ZNRD1 could enhance the resistance of EC109 cells to chemotherapeutics and suppress the apoptosis. ZNRD1-expressing EC109 cells exhibited a significant enhanced DNA repair capacity, and the overexpression of ZNRD1 could upregulate the expression of excision repair cross-complementing 1 (ERCC1) gene. Thus suggested ZNRD1 might play an important role in the process of DNA damage and repair by regulating the expression of ERCC1. In addition, the ZNRD1 gene might be involved in the cisplatin resistance of EC109 cells by regulating the expression of ERCC1 and Bcl-2.
引文
1. Stathopoulos GP, Tsiaras N. Epidemiology and pathogenesis of esophageal cancer: management and its controversial results. Oncol Rep, 2003,10(2):449-454.
2.贺宇彤,侯浚,陈志峰,等.河北省磁县近三十年食管癌发病死亡趋势分析.中华流行病学杂志, 2006,27(2):127-131.
3. Ries LAG, Eisner MP, Kosary C, et al, eds. SEER cancer statistics review, 1973-1999. Bethesda, Md.: National Cancer Institute, 2002.
4. Pera M, Trastek VF, Carpenter HA, et al. Barrett’s esophagus with high-grade dysplasia: an indication for esophagectomy? Ann Thorac Surg, 1992,54(2):199-204.
5. Headrick JR, Nichols FC III, Miller DL, et al. High-grade esophageal dysplasia: longterm survival and quality of life after esophagectomy. Ann Thorac Surg, 2002,73(6):1697-1702.
6. Reed CE. Surgical management of esophageal carcinoma. Oncologist, 1999,4(2): 95-105.
7. Enzinger PC, Ilson DH, Kelsen DP. Chemotherapy in esophageal cancer. Semin Oncol, 1999,26(5 Suppl 15):12-20.
8.邵令方,高宗人,卫功铨,等.食管癌和贲门癌的外科治疗.中华外科杂志, 2001, 1(39):44-46.
9.张合林,平育敏,杜喜群,等.应用Cox模型分析影响食管癌切除术后的预后因素.中华肿瘤杂志, 1999,21(1):32-34.
10.李保田,阎水长,张清春,等.食管癌贲门癌术后吻合口瘘的预防.中华胸心血管外科杂志, 1996,12(6):339-341.
11. Fan W, Wang Z, Kyzysztof F, et al. A new zinc ribbon gene (ZNRD1) is cloned from the human MHC class I region. Genomics, 2000,63(1):139-141.
12. Hampsey M. Molecular genetics of the RNA polymerase II general transcriptional machinery. Microbiol Mol Biol Rev, 1998,62(2):465-503.
13. Chen HT, Legault P, Glushka J, et al. Structure of a (Cys3His) zinc ribbon, a ubiquitous motif in archaeal and eucaryal transcription. Protein Sci, 2000,9(9):1743-1752.
14. Grishin NV. C-terminal domains of Escherichia coli topoisomerase I belong to the zinc-ribbon superfamily. J Mol Biol, 2000,299(5):1165-1177.
15. Zhao Y, You H, Liu F, et al. Differentially expressed gene profiles between multidrug resistant gastric adenocarcinoma cells and their parental cells. Cancer letters, 2002,185(2):211-218.
16. Zhang YM, Zhao YQ, Pan YL, et al. Effect of ZNRD1 gene antisense RNA on drug resistantgastric cancer cells. World J Gastroenterol, 2003,9:894-898.
17. Shi Y, Zhang Y, Zhao Y, et al. Overexpression of ZNRD1 promotes multidrug-resistant phenotype of gastric cancer cells through upregulation of P-glycoprotein. Cancer Biol Ther, 2004,3(4):377-381.
18. Hong L, Zhang YM, Liu N, et al. Suppression of the cell proliferation in stomach cancer cells by the ZNRD1 gene. Biochem Biophys Res Commun, 2004,321:611-616.
19. Kumar A, Chatopadhyay T, Raziuddin M, et al. Discovery of deregulation of zinc homeostasis and its associated genes in esophageal squamous cell carcinoma using cDNA microarray. Int J Cancer, 2007,15;120(2):230-242.
20. Hong L, Zhang Y, Han S, et al. Preparation and characterization of a novel monoclonal antibody specific to human ZNRD1 protein. Hybrid Hybridomics, 2004,23(l):65-68.
21. Hong L, Han Y, Shi R, et al. ZNRD1 gene suppresses cell proliferation through cell cycle arrest in G1 phase. Cancer Biol Ther, 2005,4(1):60-64.
22.赵晓红,郭新宁,翟惠虹,等. ZNRD1在肝癌中的表达及对HepG2细胞增殖的影响.中国肿瘤, 2005,14(1):53-55.
23.艾军魁,张志文,辛殿棋,等.抑制消减杂交结合cDNA微阵列技术鉴定人肾癌组织高表达基因谱.中国科学C辑, 2003,33(5):436-445.
24. Vallb?hmer D, Lenz HJ. Predictive and prognostic molecular markers in outcome of esophageal cancer. Dis esophagus, 2006,19(6):425-432.
25. Kuwahara M, Hirai T, Yoshida K, et al. p53, p21(Waf1/Cip1) and cyclin D1 protein expression and prognosis in esophageal cancer. Dis Esophagus, 1999,12(2):116-119.
26. Inada S, Koto T, Futami K, et al. Evaluation of malignancy and the prognosis of esophageal cancer based on an immunohistochemical study (p53, E-cadherin, epidermal growth factor receptor). Surg Today, 1999,29(6):493-503.
27. Brattstr?m D, Wagenius G, Sandstr?m P, et al. Newly developed assay measuring cytokeratins 8, 18 and 19 in serum is correlated to survival and tumor volume in patients with esophageal carcinoma. Dis Esophagus, 2005,18(5):298-303.
28. Brockmann JG, St Nottberg H, Glodny B, et al. CYFRA 21-1 serum analysis in patients with esophageal cancer. Clin Cancer Res, 2000,6(11):4249-4252.
29. Shimada H, Nabeya Y, Okazumi S, et al. Prognostic significance of CYFRA 21-1 in patients with esophageal squamous cell carcinoma. J Am Coll Surg, 2003,196(4): 573-578.
30. Chu TW, Capossela A, Coleman R, et al. Cloning of a new "finger" protein gene (ZNF173) within the class I region of the human MHC. Genomics, 1995,29(1): 229-239.
31. Qian X, Jeon C, Yoon H, et al. Structure of a new nucleic-acid-binding motif in eukaryotic transcriptional elongation factor TFIIS. Nature, 1993,365(6443):277-279.
32. Ha I, Lane WS, Reinberg D, et al. Cloning of a human gene encoding the general transcription initiation factor IIB. Nature, 1991,352(6337):689-695.
33. Pinto I, Ware DE, Hampsey M, et al. The yeast SUA7 gene encodes a homolog of human transcription factor TFIIB and is required for normal start site selection in vivo. Cell, 1992,68(5):977-988.
34. Wampler SL, Kadonaga JT. Functional analysis of Drosophila transcription factor IIB. Genes Dev, 1992,6(8):1542-1552.
35. Hong L, Chen Z, Zhang X, et al. Zinc ribbon domain containing 1 protein: modulator of multidrug resistance, tumorigenesis and cell cycle. Exp Oncol, 2006,28(4):258-262.
36. Igaki H, Kato H, Tachimori Y, et al. Prognostic evaluation of patients with clinical T1 and T2 squamous cell carcinomas of the thoracic esophagus after 3-field lymph node dissection. Surgery, 2003,133(4):368-374.
37. Ogata Y, Fujita H, Yamana H, et al. Expression of vascular endothelial growth factor as a prognostic factor in node-positive squamous cell carcinoma in the thoracic esophagus: long-term follow-up study. World J Surg, 2003,27(5):584-589.
38. Brucher BL, Becker K, Lordick F, et al. The clinical impact of histopathologic response assessment by residual tumor cell quantification in esophageal squamous cell carcinomas. Cancer, 2006,106(10):2119-2127.
39. Raja S, Luketich JD, Kelly LA, et al. Rapid, quantitative reverse transcriptase- polymerase chain reaction: application to intraoperative molecular detection of occult metastases in esophageal cancer. J Thorac Cardiovasc Surg, 2002,123(3):475-482.
40. Godfrey TE, Raja S, Finkelstein SD, et al. Prognostic value of quantitative reverse transcription-polymerase chain reaction in lymph node-negative esophageal cancer patients. Clin Cancer Res, 2001,7(12):4041-4048.
41. Hosch S, Kraus J, Scheunemann P, et al. Malignant potential and cytogenetic characteristics of occult disseminated tumor cells in esophageal cancer. Cancer Res, 2000,60(24):6836-6840.
42. Ikeda M, Natsugoe S, Ueno S, et al. Significant host- and tumor-related factors for predicting prognosis in patients with esophageal carcinoma. Ann Surg, 2003, 238(2):197-202.
43. Zhang MJ. Cox proportional hazards regression models for survival data in cancer research. Cancer Treat Res, 2002,l13(1):59-70.
44. Goan YG, Chang HC, Hsu HK, et al. An audit of surgical outcomes of esophageal squamous cell carcinoma. Eur J Cardiothorac Surg, 2007,31(3):536-544.
45.黄志刚,范增林,李学民,等.食管癌切除术后患者预后的Cox回归分析.中国公共卫生, 2005,21(7):784-785.
46. Petrequin P, Huguier M, Lacaine F, et al. Surgicallytreated esophageal cancers: predictive model of survival. Gastroenterol Clin Biol, 1997,21(1):12-16.
47. Hong L, Han Y, Han Y, et al. Mechanisms of growth arrest by zinc ribbon domain-containing 1 (ZNRD1) in gastric cancer cells. Carcinogenesis, 2007,28(8): 1622-1628.
48.高川,王惠芳,张靖.脂质体介导转染法的原理与应用.生命的化学, 2002, 22(1):73-75.
49.张宇梅,赵燕秋,严泉剑,等.锌带基因ZNRD1在胃癌耐药细胞中的表达和功能.中华肿瘤杂志, 2003,25(2):125-129.
50.张宇梅,时永全,金晓航,等. ZNRD1的抗体制备及在胃癌耐药细胞的蛋白表达.中国免疫学杂志, 2003,5:325-327.
51. Hong L, Piao Y, Han Y, et al. Zinc ribbon domain-containing 1 (ZNRD1) mediates multidrug resistance of leukemia cells through regulation of P-glycoprotein and Bcl-2. Mol Cancer Ther, 2005,4(12):1936-1942.
52. Gebski V, Burmeister B, Smithers BM, et al, for the Australasian Gastro-Intestinal Trials Group. Survival benefits from neoadjuvant chemoradiotherapy or chemotherapyin oesophageal carcinoma: a meta-analysis. Lancet Oncol, 2007,8(3):226-234.
53. Burmeister BH, Smithers BM, Gebski B, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol, 2005,6(9):659-668.
54. McKelvey-Martin VJ, MHL Green P, Schmezer BL, et al. The single cell gel electrophoresis assay COMET assay: A European review. Mutation Res, 1993, 288(1):47-63.
55. Fairbairn DW, Olive PL, O'Neill KL. The comet assay: a comprehensive review. Mutat Res, 1995,339(1):37-59.
56. Singh NP, McCoy MT, Tice RR, et al. A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res, 1988,175(1):184-191.
57. Wollowski I, Ji ST, Bakalinsky AT, et al. Bacteria used for the production of yogurt inactivate carcinogens and prevent DNA damage in the colon of rats. J Nutr, 1999,129(1):77-82.
58. Rosell R, Lord RV, Taron M, et al. DNA repair and cisplatin resistance in non-small-cell lung cancer. Lung cancer, 2002,38(3):217-227.
59. Collins AR, Ma AG, Duthie SJ. The kinetics of repair of oxidative DNA damage (strand breaks and oxidised pyrimidines) in human cells. Mutat Res, 1995,336(1):69-77.
60. Visvardis EE, Tassiou AM, Piperakis SM. Study of DNA damage induction and repair capacity of fresh and cryopreserved lymphocytes exposed to H2O2 and g-irradiation with the alkaline comet assay. Mutat Res, 1997,383(1):71-80.
61. Fodor SP, Read JL, Pirrung MC, et al. Light-directed, spatially addressable parallel chemical synthesis. Science, 1991,251(4995):767-773.
62. Litman T, Druley TE, Stein WD, et al. From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance. Cell Mol Life Sci, 2001,58(7):931-959.
63. Szymkowski DE, Yarema K, Essigmann JM, et al. An intrastrand d(GpG) platinum crosslink in duplex M13 DNA is refractory to repair by human cell extracts. Proc Natl Acad Sci USA, 1992,89(22):10772-10776.
64. Gosland M, Lum B, Schimmelpfennig J, et al. Insights into mechanisms of cisplatin resistance and potential for its clinical reversal. Pharmacotherapy, 1996,16(1):16-39.
65. Reardon JT, Vaisman A, Chaney SG, et al. Efficient nucleotide excision repair of cisplatin, oxaliplatin, and bis-acetoammine-dichloro-cyclohexylamine-platinum (IV) (JM216) platinum intrastrand DNA diadducts. Cancer Res, 1999,59(16):3968-3971.
66. de Boer J, Hoeijmakers JH. Nucleotide excision repair and human syndromes. Carcinogenesis, 2000,21(3):453-460.
67. Li Q, Yu JJ, Mu C, et al. Association between the level of ERCC-1 expression and the repair of cisplatin-induced DNA damage in human ovarian cancer cells. Anticancer Res, 2000,20(2A):645-652.
68. Metzger R, Leichman CG, Danenberg KD, et al. ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. J Clin Oncol, 1998,16(1):309-316.
69. Welsh C, Day R, McGurk C, et al. Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines. Int J Cancer, 2004,110(3):352-361.
70. Chang IY, Kim MH, Kim HB, et al. Small interfering RNA-induced suppression of ERCC1 enhances sensitivity of human cancer cells to cisplatin. Biochem Biophys Res Commun, 2005,327(1):225-233.
71. Reed JC. Dysregulation of apoptosis in cancer. J Clin Oncol, 1999,17(9):2941-2953.
72. Warnecke-Eberz U, Metzger R, Miyazono F, et al. High specificity of quantitative excision repair cross-complementing 1 messenger RNA expression for prediction of minor histopathological response to neoadjuvant radiochemotherapy in esophageal cancer. Clin Cancer Res, 2004,10(11):3794-3799.
73. Cobo M, Isla D, Massuti B, et al. Customizing cisplatin based on quantitative excision repair cross-completementing 1 mRNA expression: A phase III randomized trial in non-small cell lung cancer. J Clin Oncol, 2007,25(19):2747-2754.
1. Moller G. HLA and disease susceptibility. Immunol Rev, 1983,70:5-218.
2. Monaco JJ, Cho S, Attaya M. Transport protein genes in the murine MHC: Possible implications for antigen processing. Science, 1990,250(4988):1723-1726.
3. Beck S, Kelly A, Radley E, et al. DNA sequence analysis of 66 kb of the human MHC class II region encoded a cluster of genes for antigen processing. J Mol Biol, 1992,228(2):433-441.
4. Gruen JR, Nalabolu SR, Chu T, et al. A transcription map of the major histocompatibility complex (MHC) class I region. Genomics, 1996,36(1):70-85.
5. Fan W, Cai W, Parimoo S, et al. Identification of seven new human MHC class I region genes around the HLA-F locus. Immunogenetics, 1996,44(2):97-103.
6. Fan W, Liu Y, Parimoo S, et al. Olfactory receptor-like genes are located in the human major histocompatibility complex. Genomics 1995,27(1):119-123.
7. Fan W, Wei X, Shukla H, et al. Application of cDNA selection techniques to regions of the human MHC. Genomics, 1993,17(3):575-581.
8. Lepourcelet M, Andrieux N, Giffon T, et al. Systematic sequencing of the human HLA-A/HLA-F region: establishment of a cosmid contig and identification of a new gene cluster within 37 kb of sequence. Genomics, 1996,37(3):316-326.
9. Ha H, Howard CA, Yeom YI, et al. Several testis-expressed genes in the mouse t-complex have expression differences between wildtype and t-mutant mice. Dev Genet, 1991,12(4):318-332.
10. Fan W, Wang Z, Kyzysztof F, et al. A new zinc ribbon gene (ZNRD1) is cloned from the human MHC class I region. Genomics, 2000;63(1):139-141.
11. Qian X, Jeon C, Yoon H, et al. Structure of a new nucleic-acid-binding motif in eukaryotic transcriptional elongation factor TFIIS. Nature, 1995,376(6537):279.
12. Qian X, Gozani SN, Yoon H, et al. Novel zinc finger motif in the basal transcriptional machinery: Three-dimensional NMR studies of the nucleic acid binding domain of transcriptional elongation factor TFIIS. Biochemistry, 1993,32(38):9944-9959.
13. Chu TW, Capossela A, Coleman R, et al. Cloning of a new“finger”protein gene (ZNF173) within the class I region of the human MHC. Genomics, 1995, 29(1):229-239.
14. Hampsey M. Molecular genetics of the RNA polymerase II general transcription machinery. Microbiol Mol Biol Rev, 1998,62(2):465-503.
15. Ha I, Lane WS, Reinberg D. Cloning of a human gene encoding the general transcription initiation factor IIB. Nature, 1991,352(6337):689-695.
16. Barberis A, Muller C, Harrison S, et al. Delineation of two functional region of transcription factor TFIIB. Proc Natl Acad Sci USA, 1993,90(12):5628-5632.
17. Lee S, Hahn S. Model for binding of transcription factor TFIIB to the TBP-DNA complex. Nature, 1995,376(6541):609-612.
18. Lagrange T, Kapanidis AN, Tang H, et al. New core promoter element in RNA polymerase II-dependent transcription: sequence-specific DNA binding by transcription factor IIB. Genes Dev, 1998,12(1):34-44.
19. Lin YS, Green MR. Mechanism of action of an acidic transcriptional activator in vitro. Cell, 1991,64(5):971-981.
20. Kim TK, Roeder RG. Proline-rich activator CTF1 targets the TFIIB assembly step during transcription activation. Proc Natl Acad Sci USA, 1994,91(10):4170-4174.
21. Wu Y, Reece R, Ptashne M. Quantitation of putative activatortarget affinities predicts transcriptional activating potentials. EMBO J, 1996,15(15):3951-3963.
22. Pinto I, Ware DE, Hampsey M. The yeast SUA7 gene encodes a homolog of human transcription factor TFIIB and is required for normal start site selection in vivo. Cell, 1992,68(5):977-988.
23. Wampler SL, Kadonaga JT. Functional analysis of Drosophila transcription factor IIB. Genes Dev, 1992,6(8):1542-1552.
24. Bagby S, Kim S, Maldonado E, et al. Solution structure of the C-terminal core domain of human TFIIB: similarity to cyclin A and interaction with TATA-binding protein. Cell, 1995,82(5):857-867.
25. Nikolov DB, Chen H, Halay ED, et al. Crystal structure of a TFIIB-TBP- TATA-element ternary complex. Nature, 1995,377(6545), 119-128.
26. Zhu W, Zeng Q, Colangelo CM, et al. The N-terminal domain of TFIIB from pyrococcus furiosus forms a zinc fibbon. Nat Strut Biol, 1996,3(2):122-124.
27. Chen HT, Legault P, Glushka J, et al. Structure of a (Cys3His) zinc ribbon, aubiquitous motif in archaeal and eucaryal transcription. Protein Sci, 2000,9(9): 1743-1752.
28. Ha I, Roberts S, Maldonado E, et al. Multiple functional domains of human transcription factor IIB: distinct interactions with two general transcription factors and RNA polymerase II. Genes Dev, 1993,7(6):1021-1032.
29. Pardee TS, Bangur CS, Ponticelli AS. The N-terminal region of yeast TFIIB contains two adjacent functional domains involved in stable RNA polymerase II binding and transcriptional start site selection. J Biol Chem, 1998,273(28):17859-17864.
30. Miller J, McLachlan AD, Klug A. Repetitive zinc-binding domains in the protein transcription factorⅢA from Xenopus oocytes. EMBO J, 1985,4(6):1609-1614.
31. Evans RM, Hollenberg SM. Zinc finger: Gilt by association. Cell, 1988,52(1):1-3.
32. Liao XB, Clemens KR, Tennant L, et al. Specific interaction of the first three zinc fingers of TFⅢA with the internal control region of the Xenopus 5S RNA gene. J Mol Biol, 1992,223(20):857-871.
33. Shi YG, Berg JM. Specific DNA-RNA hybrid binding by zinc finger proteins. Science, 1995,268(14):282-284.
34. Lee JS, Galvin KM, Shi Y. Evidence for physical interaction between the zinc-finger transcription factors YY1 and Sp11. Proc Natl Acad Sci USA, 1993,90(13):6145-6149.
35. Krishna SS, Majumda I, Grishin NV. Structural classification of zinc fingers. Nucleic Acids Research, 2003,31(2):532-550.
36.孙燕,苟德明,李文鑫. C2H2型锌指蛋白研究进展.生命的化学, 2001,6(21): 473-475.
37. Somers WS, Phillips SE. Crystal structure of the met repressor-operator complex at 2.8 A resolution reveals DNA recognition by beta-strands. Nature, 1992,359(6394): 387-393.
38. Nikolov DB, Hu SH, Lin J, et al. Crystal structure of TFIID TATA-box binding protein. Nature, 1992,360(6399):40-46.
39. Grishin NV. C-terminal domains of Escherichia coli topoisomerase I belong to the zinc-ribbon superfamily. J Mol Biol, 2000,299(5):1165-1177.
40. Jeon C, Yoon H, Agarwal K. The transcription factor TFIIS zinc ribbon dipeptide Asp-Glu is critical for stimulation of elongation and RNA cleavage by RNApolymerase II. Proc Natl Acad Sci, 1994,91(19):9106-9110.
41. Yoon H, Sitikov AS, Jeon C, et al. Preferential interaction of the mRNA proofreading factor TFIIS zinc ribbon with rU.dA base pairs correlates with its function. Biochemistry, 1998,37(35):12104-12112.
42. Wang B, Jones DN, Kaine BP, et al. High-resolution structure of an archaeal zinc ribbon defines a general architectural motif in eukaryotic RNA polymerases. Structure, 1998,6(5):555-569.
43. Hemming SA, Jansma DB, Macgregor PF, et al. RNA polymerase II subunit Rpb9 regulates transcription elongation in vivo. J Biol Chem, 2000,275(45):35506-35511.
44. Spakovskii GV, Lebedenko EN. Molecular identification and characteristics of hRPC11, the smallest specific subunit of human RNA polymerase III. Bioorg Khim, 1998,24(11):877-880.
45. Cabart P, Murphy S. Assembly of human small nuclear RNA gene-specific transcription factor IIIB complex de novo on and off promoter. J Biol Chem, 2002,277(30): 26831-26838.
46. Hong L, Han Y, Shi R, et al. ZNRD1 gene suppresses cell proliferation through cell Cycle arrest in G1 phase. Cancer Biol Ther, 2005,4(1):60-64.
47. Hong L, Han Y, Han Y, et al. Mechanisms of growth arrest by zinc ribbon domain-containing 1 (ZNRD1) in gastric cancer cells. Carcinogenesis, 2007, 28(8):1622-1628.
48. Hayes JD, Wolf CR. Molecular mechanisms of drug resistance. Biochem J, 1990,272(2):281-295.
49. Arceci RJ. Clinical significance of P-Glycoprotein in multidrug resistance malignancies. Blood, 1993,81(9):2215-2222.
50. Gottesman MM, Hrycyna CA. Genetic analysis of the multidrug transporter. Annu Rev Genet, 1995,29:607-649.
51. McCoy C, McGee SB, Cornwell MM. The Wilms' tumor suppressor, WTl,imhibits 120 tetradecanoylphirbol 13 acetate activation of the multidrug resistance 1 promoter. Cell Growth Differ, 1999,10(6):377-386.
52. Bartsevich VV, Juliano RL. Regulation of the MDR1 gene by transcriptional repressors selected using peptide combinatorial libraries. Mol Pharmacol, 2000,58(1):1-10.
53. Hong L, Piao Y, Han Y, et al. Zinc ribbon domain-containing 1 (ZNRD1) mediates multidrug resistance of leukemia cells through regulation of P-glycoprotein and Bcl-2. Mol Cancer Ther, 2005,4(12):1936-1942.
54.张宇梅,赵燕秋,严泉剑,等.锌带基因ZNRD1在胃癌耐药细胞中的表达和功能.中华肿瘤杂志, 2003,25(2):125-129.
55.张宇梅,时永全,金晓航,等. ZNRD1的抗体制备及在胃癌耐药细胞的蛋白表达.中国免疫学杂志, 2003,19(05):325-327.
56. Shi Y, Zhang Y, Zhao Y, et al. Overexpression of ZNRDl promotes multidrug-resistant phenotype of gastric cancer cells through upregulation of P-glycoprotein. Cancer Biol Ther, 2004,3(4):377-381.
57. Hong L, Wang J, Han Y, et al. Reversal of multidrug resistance of vincristine-resistant gastric adenocarcinoma cells through up-regulation of DARPP-32. Cell Biol Int, 2007,31(9):1010-1015.
58. Bartsevich VV, Iuliano RL. Regulation of the MDR1 gene by transcriptional repressors selected using peptide combinatorial libraries. Mol Pharmacol, 2000,58(1):1-10.
59. Ai J, Zhang Z, Xin D, et al. Identification of over-expressed genes in human renal cell carcinoma by combining suppression subtractive hybridization and cDNA library array. Sci China C Life Sci, 2004,47(2):148-157.
60. Kumar A, Chatopadhyay T, Raziuddin M, et al. Discovery of deregulation of zinc homeostasis and its associated genes in esophageal squamous cell carcinoma using cDNA microarray. Int J Cancer, 2007,120(2):230-242.
61. Hong L, Zhang Y, Han S, et al. Preparation and characterization of a novel monoclonal antibody specific to human ZNRD1 protein. Hybrid Hybridomics, 2004,23(l):65-68.
62.赵晓红,郭新宁,翟惠虹,等. ZNRD1在肝癌中的表达及对HepG2细胞增殖的影响.中国肿瘤, 2005,14(1):53-55.
63.艾军魁,张志文,辛殿棋,等.抑制消减杂交结合cDNA微阵列技术鉴定人肾癌组织高表达基因谱.中国科学C辑, 2003,33(5):436-445.
1. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin, 2005,55(2):74-108.
2. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med, 2003,349(23):2241-2252.
3. Yang CS. Research on esophageal cancer in China. Cancer Res, 1980,40(8 Pt 1):2633-2644.
4. van Rensburg SJ. Epidemiologic and dietary evidence for a specific nutritional predisposition to esophageal cancer. J Natl Cancer Inst, 1981,67(2):243-251.
5. Abnet CC, Lai B, Qiao YL, et al. Zinc concentration in esophageal biopsy specimens measured by X-ray fluorescence and esophageal cancer risk. J Natl Cancer Inst, 2005,97(4):301-306.
6. Mu?oz N, Crespi M, Grassi A, et al. Precursor lesions of oesophageal cancer in high-risk populations in Iran and China. Lancet, 1982,17(1):876-879.
7. Sky Peck HH. Trace metals and neoplasia. Clin Physiol Biochem, 1986,4(1):99-111.
8. Vallee BL, Falchuk KH. The biochemical basis of zinc physiology. Physiol-Rev, 1993,73(1):79-118.
9. Fong LY, Sivak A, Newberne PM. Zinc deficiency and methylbenzylnitrosamine- induced esophageal cancer in rats. J Natl Cancer Inst, 1978,61(1):145-150.
10. Fong LY, Li JX, Farber JL, et al. Cell proliferation and esophageal carcinogenesis in the zinc-deficient rat. Carcinogenesis, 1996,17(9):1841-1848.
11. Fong LY, Ishii H, Nguyen VT, et al. p53 deficiency accelerates induction and progression of esophageal and forestomach tumors in zinc-deficient mice. Cancer Res, 2003,63(1):186-195.
12. Lipman TO, Diamond A, Mellow MH, et al. Esophageal zinc content in human squamous esophageal cancer. J Am Coll Nutr, 1987,6(1):41-46.
13. Kumar A, Chatopadhyay T, Raziuddin M, et al. Discovery of deregulation of zinc homeostasis and its associated genes in esophageal squamous cell carcinoma using cDNA microarray. Int J Cancer, 2007,120(2):230-242.
14. Varmeh-Ziaie S, Ichimura K, Yang F, et al. Cloning and chromosomal localization of human WIG-1/PAG608 and demonstration of amplification with increased expressionin primary squamous cell carcinoma of the lung. Cancer Lett, 2001,174(2):179-187.
15. Méndez Vidal C, Prahl M, Wiman KG. The p53-induced Wig-1 protein binds double-stranded RNAs with structural characteristics of siRNAs and miRNAs. FEBS Lett, 2006,580(18):4401-4408.
16. Hellborg F, Wiman KG. The p53-induced Wig-1 zinc finger protein is highly conserved from fish to man. Int J Oncol, 2004,24(6):1559-1564.
17. Brass N, Racz A, Heckel D, et al. Amplification of the genes BCHE and SLC2A2 in 40% of squamous cell carcinoma of the lung. Cancer Res, 1997,57(11):2290-2294.
18. Sattler HP, Lensch R, Rohde V, et al. Novel amplification unit at chromosome 3q25-q27 in human prostate cancer. Prostate, 2000,45(3):207-215.
19. Lazo PA. The molecular genetics of cervical carcinoma. Br J Cancer, 1999, 80(12):2008-2018.
20. Hibi K, Trink B, Patturajan M, et al. AIS is an oncogene amplified in squamous cell carcinoma. Proc Natl Acad Sci USA, 2000,97(10):5462-5467.
21. Sugita M, Tanaka N, Davidson S, et al. Molecular definition of a small amplification domain within 3q26 in tumors of cervix, ovary, and lung, Cancer Genet. Cytogenet, 2000,117(1):9-18.
22. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell, 1997, 88(3):323-331.
23. Lane DP. Cancer. p53, guardian of the genome. Nature, 1992,358(6381):15-16.
24. Hollstein M, Sidransky D, Vogelstein B, et al. p53 mutations in human cancers. Science, 1991,253(5015):49-53.
25. Bedwal RS, Bahuguna A. Zinc, copper and selenium in reproduction. Experientia, 1994,50(7):626-640.
26. Pavletich NP, Chambers KA, Pabo CO. The DNA-binding domain of p53 contains the four conserved regions and the major mutation hot spots. Genes Dev, 1993, 7(12B):2556-2564.
27. Ho E, Ames BN. Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFkappaB and AP1 binding and affects DNA repair in a rat glioma cell line. Proc Natl Acad Sci U S A, 2002,99(26):16770-16775.
28. Fritz G. Human APE/Ref-1 protein. Int J Biochem Cell Biol, 2000,32(9):925-929.
29. Evans AR, Limp-Foster M, Kelley MR. Going APE over ref-1. Mutat Res, 2000,461(2):83-108.
30. Fraker PJ, Jardieu P, Cook J. Zinc deficiency and immune function. Arch Dermatol, 1987,123(12):1699-1701.
31. Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol, 1994,10:405-455.
32. Shaulian E, Karin M. AP-1 in cell proliferation and survival. Oncogene, 2001,20(19):2390-2400.
33. Hennig B, Meerarani P, Ramadass P, et al. Zinc nutrition and apoptosis of vascular endothelial cells: implications in atherosclerosis. Nutrition, 1999,15(10):744-748.
34. Truong-Tran AQ, Carter J, Ruffin RE, et al. The role of zinc in caspase activation and apoptotic cell death. Biometals, 2001,14(3-4):315-330.
35. Nakatani T, Tawaramoto M, Opare Kennedy D, et al. Apoptosis induced by chelation of intracellular zinc is associated with depletion of cellular reduced glutathione level in rat hepatocytes. Chem Biol Interact, 2000,125(3):151-163.
36. Oteiza PI, Clegg MS, Keen CL. Short-term zinc deficiency affects nuclear factor-kappab nuclear binding activity in rat testes. J Nutr, 2001,131(1):21-26.
37. Ho E. Zinc deficiency, DNA damage and cancer risk. J Nutr Biochem, 2004, 15(10):572-578.
38. Federico A, Iodice P, Federico P, et al. Effects of selenium and zinc supplementation on nutritional status in patients with cancer of digestive tract. Eur J Clin Nutr, 2001,55(4):293-297.
39. Prasad AS, Beck FW, Doerr TD, et al. Nutritional and zinc status of head and neck cancer patients: an interpretive review. J Am Coll Nutr, 1998,17(5):409-418.
40. Oteiza PI, Clegg MS, Zago MP, et al. Zinc deficiency induces oxidative stress and AP-1 activation in 3T3 cells. Free Radic Biol Med, 2000,28(7):1091-1099.
41. Golub MS, Gershwin ME, Hurley LS, et al. Studies of marginal zinc deprivation in rhesus monkeys: infant behavior. Am J Clin Nutr, 1985,42(6):1229-1239.
42. Fong LY, Lau KM, Huebner K, et al. Induction of esophageal tumors in zinc-deficient rats by single low doses of N-nitrosomethyl-benzylamine (NMBA): analysis of cell proliferation, and mutations in H-ras and p53 genes. Carcinogenesis, 1997,18(8):1477-1484.
43. Fong LY, Magee PN. Dietary zinc deficiency enhances esophageal cell proliferation and N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumor incidence in C57BL/6 mouse. Cancer Lett, 1999,143(1):63-69.
44. Newberne PM, Schrager TF, Broitman S. Esophageal carcinogenesis in the rat: zinc deficiency and alcohol effects on tumor induction. Pathobiology, 1997,65(1):39-45.
45. Oteiza PI, Olin KL, Fraga CG, et al. Zinc deficiency causes oxidative damage to proteins, lipids and DNA in rat testes. J Nutr, 1995,125(4):823-829.
46. Costello LC, Franklin RB. Novel role of zinc in the regulation of prostate citrate metabolism and its implications in prostate cancer. Prostate, 1998,35(4):285-296.
47. Costello LC, Franklin RB. The intermediary metabolism of the prostate: a key to understanding the pathogenesis and progression of prostate malignancy. Oncology, 2000,59(4):269-282.
48. Kristal AR, Stanford JL, Cohen JH, et al. Vitamin and mineral supplement use is associated with reduced risk of prostate cancer. Cancer Epidemiol Biomarkers Prev, 1999,8(10):887-892.
49. Lu H, Cai L, Mu LN, et al. Dietary mineral and trace element intake and squamous cell carcinoma of the esophagus in a Chinese population. Nutr Cancer, 2006,55(1):63-70.
50. John DH, David AC. Role of Integrins in Cell Invasion and Migration. Nat Cancer Rev, 2002,2(2):91-100.
51. Oue N, Aung PP, Mitani Y, et al. Genes involved in invasion and metastasis of gastric cancer identified by array-based hybridization and serial analysis of gene expression. Oncology, 2005,69(Suppl 1):17-22.
52. Israeli D, Tessler E, Haupt Y, et al. A novel p53-inducible gene, PAG608, encodes a nuclear zinc finger protein whose overexpression promotes apoptosis. EMBO J, 1997,16(14):4384-4392.
53. Varmeh-Ziaie S, Okan I, Wang Y, et al. Wig-1, a new p53-induced gene encoding a zinc finger protein. Oncogene, 1997,15(22):2699-2704.
54. Wilhelm MT, Méndez-Vidal C, Wiman KG. Identification of functional p53-binding motifs in the mouse wig-1 promoter. FEBS Lett, 2002,524(1-3):69-72.
2.贺宇彤,侯浚,陈志峰,等.河北省磁县近三十年食管癌发病死亡趋势分析.中华流行病学杂志, 2006,27(2):127-131.
3. Ries LAG, Eisner MP, Kosary C, et al, eds. SEER cancer statistics review, 1973-1999. Bethesda, Md.: National Cancer Institute, 2002.
4. Pera M, Trastek VF, Carpenter HA, et al. Barrett’s esophagus with high-grade dysplasia: an indication for esophagectomy? Ann Thorac Surg, 1992,54(2):199-204.
5. Headrick JR, Nichols FC III, Miller DL, et al. High-grade esophageal dysplasia: longterm survival and quality of life after esophagectomy. Ann Thorac Surg, 2002,73(6):1697-1702.
6. Reed CE. Surgical management of esophageal carcinoma. Oncologist, 1999,4(2): 95-105.
7. Enzinger PC, Ilson DH, Kelsen DP. Chemotherapy in esophageal cancer. Semin Oncol, 1999,26(5 Suppl 15):12-20.
8.邵令方,高宗人,卫功铨,等.食管癌和贲门癌的外科治疗.中华外科杂志, 2001, 1(39):44-46.
9.张合林,平育敏,杜喜群,等.应用Cox模型分析影响食管癌切除术后的预后因素.中华肿瘤杂志, 1999,21(1):32-34.
10.李保田,阎水长,张清春,等.食管癌贲门癌术后吻合口瘘的预防.中华胸心血管外科杂志, 1996,12(6):339-341.
11. Fan W, Wang Z, Kyzysztof F, et al. A new zinc ribbon gene (ZNRD1) is cloned from the human MHC class I region. Genomics, 2000,63(1):139-141.
12. Hampsey M. Molecular genetics of the RNA polymerase II general transcriptional machinery. Microbiol Mol Biol Rev, 1998,62(2):465-503.
13. Chen HT, Legault P, Glushka J, et al. Structure of a (Cys3His) zinc ribbon, a ubiquitous motif in archaeal and eucaryal transcription. Protein Sci, 2000,9(9):1743-1752.
14. Grishin NV. C-terminal domains of Escherichia coli topoisomerase I belong to the zinc-ribbon superfamily. J Mol Biol, 2000,299(5):1165-1177.
15. Zhao Y, You H, Liu F, et al. Differentially expressed gene profiles between multidrug resistant gastric adenocarcinoma cells and their parental cells. Cancer letters, 2002,185(2):211-218.
16. Zhang YM, Zhao YQ, Pan YL, et al. Effect of ZNRD1 gene antisense RNA on drug resistantgastric cancer cells. World J Gastroenterol, 2003,9:894-898.
17. Shi Y, Zhang Y, Zhao Y, et al. Overexpression of ZNRD1 promotes multidrug-resistant phenotype of gastric cancer cells through upregulation of P-glycoprotein. Cancer Biol Ther, 2004,3(4):377-381.
18. Hong L, Zhang YM, Liu N, et al. Suppression of the cell proliferation in stomach cancer cells by the ZNRD1 gene. Biochem Biophys Res Commun, 2004,321:611-616.
19. Kumar A, Chatopadhyay T, Raziuddin M, et al. Discovery of deregulation of zinc homeostasis and its associated genes in esophageal squamous cell carcinoma using cDNA microarray. Int J Cancer, 2007,15;120(2):230-242.
20. Hong L, Zhang Y, Han S, et al. Preparation and characterization of a novel monoclonal antibody specific to human ZNRD1 protein. Hybrid Hybridomics, 2004,23(l):65-68.
21. Hong L, Han Y, Shi R, et al. ZNRD1 gene suppresses cell proliferation through cell cycle arrest in G1 phase. Cancer Biol Ther, 2005,4(1):60-64.
22.赵晓红,郭新宁,翟惠虹,等. ZNRD1在肝癌中的表达及对HepG2细胞增殖的影响.中国肿瘤, 2005,14(1):53-55.
23.艾军魁,张志文,辛殿棋,等.抑制消减杂交结合cDNA微阵列技术鉴定人肾癌组织高表达基因谱.中国科学C辑, 2003,33(5):436-445.
24. Vallb?hmer D, Lenz HJ. Predictive and prognostic molecular markers in outcome of esophageal cancer. Dis esophagus, 2006,19(6):425-432.
25. Kuwahara M, Hirai T, Yoshida K, et al. p53, p21(Waf1/Cip1) and cyclin D1 protein expression and prognosis in esophageal cancer. Dis Esophagus, 1999,12(2):116-119.
26. Inada S, Koto T, Futami K, et al. Evaluation of malignancy and the prognosis of esophageal cancer based on an immunohistochemical study (p53, E-cadherin, epidermal growth factor receptor). Surg Today, 1999,29(6):493-503.
27. Brattstr?m D, Wagenius G, Sandstr?m P, et al. Newly developed assay measuring cytokeratins 8, 18 and 19 in serum is correlated to survival and tumor volume in patients with esophageal carcinoma. Dis Esophagus, 2005,18(5):298-303.
28. Brockmann JG, St Nottberg H, Glodny B, et al. CYFRA 21-1 serum analysis in patients with esophageal cancer. Clin Cancer Res, 2000,6(11):4249-4252.
29. Shimada H, Nabeya Y, Okazumi S, et al. Prognostic significance of CYFRA 21-1 in patients with esophageal squamous cell carcinoma. J Am Coll Surg, 2003,196(4): 573-578.
30. Chu TW, Capossela A, Coleman R, et al. Cloning of a new "finger" protein gene (ZNF173) within the class I region of the human MHC. Genomics, 1995,29(1): 229-239.
31. Qian X, Jeon C, Yoon H, et al. Structure of a new nucleic-acid-binding motif in eukaryotic transcriptional elongation factor TFIIS. Nature, 1993,365(6443):277-279.
32. Ha I, Lane WS, Reinberg D, et al. Cloning of a human gene encoding the general transcription initiation factor IIB. Nature, 1991,352(6337):689-695.
33. Pinto I, Ware DE, Hampsey M, et al. The yeast SUA7 gene encodes a homolog of human transcription factor TFIIB and is required for normal start site selection in vivo. Cell, 1992,68(5):977-988.
34. Wampler SL, Kadonaga JT. Functional analysis of Drosophila transcription factor IIB. Genes Dev, 1992,6(8):1542-1552.
35. Hong L, Chen Z, Zhang X, et al. Zinc ribbon domain containing 1 protein: modulator of multidrug resistance, tumorigenesis and cell cycle. Exp Oncol, 2006,28(4):258-262.
36. Igaki H, Kato H, Tachimori Y, et al. Prognostic evaluation of patients with clinical T1 and T2 squamous cell carcinomas of the thoracic esophagus after 3-field lymph node dissection. Surgery, 2003,133(4):368-374.
37. Ogata Y, Fujita H, Yamana H, et al. Expression of vascular endothelial growth factor as a prognostic factor in node-positive squamous cell carcinoma in the thoracic esophagus: long-term follow-up study. World J Surg, 2003,27(5):584-589.
38. Brucher BL, Becker K, Lordick F, et al. The clinical impact of histopathologic response assessment by residual tumor cell quantification in esophageal squamous cell carcinomas. Cancer, 2006,106(10):2119-2127.
39. Raja S, Luketich JD, Kelly LA, et al. Rapid, quantitative reverse transcriptase- polymerase chain reaction: application to intraoperative molecular detection of occult metastases in esophageal cancer. J Thorac Cardiovasc Surg, 2002,123(3):475-482.
40. Godfrey TE, Raja S, Finkelstein SD, et al. Prognostic value of quantitative reverse transcription-polymerase chain reaction in lymph node-negative esophageal cancer patients. Clin Cancer Res, 2001,7(12):4041-4048.
41. Hosch S, Kraus J, Scheunemann P, et al. Malignant potential and cytogenetic characteristics of occult disseminated tumor cells in esophageal cancer. Cancer Res, 2000,60(24):6836-6840.
42. Ikeda M, Natsugoe S, Ueno S, et al. Significant host- and tumor-related factors for predicting prognosis in patients with esophageal carcinoma. Ann Surg, 2003, 238(2):197-202.
43. Zhang MJ. Cox proportional hazards regression models for survival data in cancer research. Cancer Treat Res, 2002,l13(1):59-70.
44. Goan YG, Chang HC, Hsu HK, et al. An audit of surgical outcomes of esophageal squamous cell carcinoma. Eur J Cardiothorac Surg, 2007,31(3):536-544.
45.黄志刚,范增林,李学民,等.食管癌切除术后患者预后的Cox回归分析.中国公共卫生, 2005,21(7):784-785.
46. Petrequin P, Huguier M, Lacaine F, et al. Surgicallytreated esophageal cancers: predictive model of survival. Gastroenterol Clin Biol, 1997,21(1):12-16.
47. Hong L, Han Y, Han Y, et al. Mechanisms of growth arrest by zinc ribbon domain-containing 1 (ZNRD1) in gastric cancer cells. Carcinogenesis, 2007,28(8): 1622-1628.
48.高川,王惠芳,张靖.脂质体介导转染法的原理与应用.生命的化学, 2002, 22(1):73-75.
49.张宇梅,赵燕秋,严泉剑,等.锌带基因ZNRD1在胃癌耐药细胞中的表达和功能.中华肿瘤杂志, 2003,25(2):125-129.
50.张宇梅,时永全,金晓航,等. ZNRD1的抗体制备及在胃癌耐药细胞的蛋白表达.中国免疫学杂志, 2003,5:325-327.
51. Hong L, Piao Y, Han Y, et al. Zinc ribbon domain-containing 1 (ZNRD1) mediates multidrug resistance of leukemia cells through regulation of P-glycoprotein and Bcl-2. Mol Cancer Ther, 2005,4(12):1936-1942.
52. Gebski V, Burmeister B, Smithers BM, et al, for the Australasian Gastro-Intestinal Trials Group. Survival benefits from neoadjuvant chemoradiotherapy or chemotherapyin oesophageal carcinoma: a meta-analysis. Lancet Oncol, 2007,8(3):226-234.
53. Burmeister BH, Smithers BM, Gebski B, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol, 2005,6(9):659-668.
54. McKelvey-Martin VJ, MHL Green P, Schmezer BL, et al. The single cell gel electrophoresis assay COMET assay: A European review. Mutation Res, 1993, 288(1):47-63.
55. Fairbairn DW, Olive PL, O'Neill KL. The comet assay: a comprehensive review. Mutat Res, 1995,339(1):37-59.
56. Singh NP, McCoy MT, Tice RR, et al. A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res, 1988,175(1):184-191.
57. Wollowski I, Ji ST, Bakalinsky AT, et al. Bacteria used for the production of yogurt inactivate carcinogens and prevent DNA damage in the colon of rats. J Nutr, 1999,129(1):77-82.
58. Rosell R, Lord RV, Taron M, et al. DNA repair and cisplatin resistance in non-small-cell lung cancer. Lung cancer, 2002,38(3):217-227.
59. Collins AR, Ma AG, Duthie SJ. The kinetics of repair of oxidative DNA damage (strand breaks and oxidised pyrimidines) in human cells. Mutat Res, 1995,336(1):69-77.
60. Visvardis EE, Tassiou AM, Piperakis SM. Study of DNA damage induction and repair capacity of fresh and cryopreserved lymphocytes exposed to H2O2 and g-irradiation with the alkaline comet assay. Mutat Res, 1997,383(1):71-80.
61. Fodor SP, Read JL, Pirrung MC, et al. Light-directed, spatially addressable parallel chemical synthesis. Science, 1991,251(4995):767-773.
62. Litman T, Druley TE, Stein WD, et al. From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance. Cell Mol Life Sci, 2001,58(7):931-959.
63. Szymkowski DE, Yarema K, Essigmann JM, et al. An intrastrand d(GpG) platinum crosslink in duplex M13 DNA is refractory to repair by human cell extracts. Proc Natl Acad Sci USA, 1992,89(22):10772-10776.
64. Gosland M, Lum B, Schimmelpfennig J, et al. Insights into mechanisms of cisplatin resistance and potential for its clinical reversal. Pharmacotherapy, 1996,16(1):16-39.
65. Reardon JT, Vaisman A, Chaney SG, et al. Efficient nucleotide excision repair of cisplatin, oxaliplatin, and bis-acetoammine-dichloro-cyclohexylamine-platinum (IV) (JM216) platinum intrastrand DNA diadducts. Cancer Res, 1999,59(16):3968-3971.
66. de Boer J, Hoeijmakers JH. Nucleotide excision repair and human syndromes. Carcinogenesis, 2000,21(3):453-460.
67. Li Q, Yu JJ, Mu C, et al. Association between the level of ERCC-1 expression and the repair of cisplatin-induced DNA damage in human ovarian cancer cells. Anticancer Res, 2000,20(2A):645-652.
68. Metzger R, Leichman CG, Danenberg KD, et al. ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. J Clin Oncol, 1998,16(1):309-316.
69. Welsh C, Day R, McGurk C, et al. Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines. Int J Cancer, 2004,110(3):352-361.
70. Chang IY, Kim MH, Kim HB, et al. Small interfering RNA-induced suppression of ERCC1 enhances sensitivity of human cancer cells to cisplatin. Biochem Biophys Res Commun, 2005,327(1):225-233.
71. Reed JC. Dysregulation of apoptosis in cancer. J Clin Oncol, 1999,17(9):2941-2953.
72. Warnecke-Eberz U, Metzger R, Miyazono F, et al. High specificity of quantitative excision repair cross-complementing 1 messenger RNA expression for prediction of minor histopathological response to neoadjuvant radiochemotherapy in esophageal cancer. Clin Cancer Res, 2004,10(11):3794-3799.
73. Cobo M, Isla D, Massuti B, et al. Customizing cisplatin based on quantitative excision repair cross-completementing 1 mRNA expression: A phase III randomized trial in non-small cell lung cancer. J Clin Oncol, 2007,25(19):2747-2754.
1. Moller G. HLA and disease susceptibility. Immunol Rev, 1983,70:5-218.
2. Monaco JJ, Cho S, Attaya M. Transport protein genes in the murine MHC: Possible implications for antigen processing. Science, 1990,250(4988):1723-1726.
3. Beck S, Kelly A, Radley E, et al. DNA sequence analysis of 66 kb of the human MHC class II region encoded a cluster of genes for antigen processing. J Mol Biol, 1992,228(2):433-441.
4. Gruen JR, Nalabolu SR, Chu T, et al. A transcription map of the major histocompatibility complex (MHC) class I region. Genomics, 1996,36(1):70-85.
5. Fan W, Cai W, Parimoo S, et al. Identification of seven new human MHC class I region genes around the HLA-F locus. Immunogenetics, 1996,44(2):97-103.
6. Fan W, Liu Y, Parimoo S, et al. Olfactory receptor-like genes are located in the human major histocompatibility complex. Genomics 1995,27(1):119-123.
7. Fan W, Wei X, Shukla H, et al. Application of cDNA selection techniques to regions of the human MHC. Genomics, 1993,17(3):575-581.
8. Lepourcelet M, Andrieux N, Giffon T, et al. Systematic sequencing of the human HLA-A/HLA-F region: establishment of a cosmid contig and identification of a new gene cluster within 37 kb of sequence. Genomics, 1996,37(3):316-326.
9. Ha H, Howard CA, Yeom YI, et al. Several testis-expressed genes in the mouse t-complex have expression differences between wildtype and t-mutant mice. Dev Genet, 1991,12(4):318-332.
10. Fan W, Wang Z, Kyzysztof F, et al. A new zinc ribbon gene (ZNRD1) is cloned from the human MHC class I region. Genomics, 2000;63(1):139-141.
11. Qian X, Jeon C, Yoon H, et al. Structure of a new nucleic-acid-binding motif in eukaryotic transcriptional elongation factor TFIIS. Nature, 1995,376(6537):279.
12. Qian X, Gozani SN, Yoon H, et al. Novel zinc finger motif in the basal transcriptional machinery: Three-dimensional NMR studies of the nucleic acid binding domain of transcriptional elongation factor TFIIS. Biochemistry, 1993,32(38):9944-9959.
13. Chu TW, Capossela A, Coleman R, et al. Cloning of a new“finger”protein gene (ZNF173) within the class I region of the human MHC. Genomics, 1995, 29(1):229-239.
14. Hampsey M. Molecular genetics of the RNA polymerase II general transcription machinery. Microbiol Mol Biol Rev, 1998,62(2):465-503.
15. Ha I, Lane WS, Reinberg D. Cloning of a human gene encoding the general transcription initiation factor IIB. Nature, 1991,352(6337):689-695.
16. Barberis A, Muller C, Harrison S, et al. Delineation of two functional region of transcription factor TFIIB. Proc Natl Acad Sci USA, 1993,90(12):5628-5632.
17. Lee S, Hahn S. Model for binding of transcription factor TFIIB to the TBP-DNA complex. Nature, 1995,376(6541):609-612.
18. Lagrange T, Kapanidis AN, Tang H, et al. New core promoter element in RNA polymerase II-dependent transcription: sequence-specific DNA binding by transcription factor IIB. Genes Dev, 1998,12(1):34-44.
19. Lin YS, Green MR. Mechanism of action of an acidic transcriptional activator in vitro. Cell, 1991,64(5):971-981.
20. Kim TK, Roeder RG. Proline-rich activator CTF1 targets the TFIIB assembly step during transcription activation. Proc Natl Acad Sci USA, 1994,91(10):4170-4174.
21. Wu Y, Reece R, Ptashne M. Quantitation of putative activatortarget affinities predicts transcriptional activating potentials. EMBO J, 1996,15(15):3951-3963.
22. Pinto I, Ware DE, Hampsey M. The yeast SUA7 gene encodes a homolog of human transcription factor TFIIB and is required for normal start site selection in vivo. Cell, 1992,68(5):977-988.
23. Wampler SL, Kadonaga JT. Functional analysis of Drosophila transcription factor IIB. Genes Dev, 1992,6(8):1542-1552.
24. Bagby S, Kim S, Maldonado E, et al. Solution structure of the C-terminal core domain of human TFIIB: similarity to cyclin A and interaction with TATA-binding protein. Cell, 1995,82(5):857-867.
25. Nikolov DB, Chen H, Halay ED, et al. Crystal structure of a TFIIB-TBP- TATA-element ternary complex. Nature, 1995,377(6545), 119-128.
26. Zhu W, Zeng Q, Colangelo CM, et al. The N-terminal domain of TFIIB from pyrococcus furiosus forms a zinc fibbon. Nat Strut Biol, 1996,3(2):122-124.
27. Chen HT, Legault P, Glushka J, et al. Structure of a (Cys3His) zinc ribbon, aubiquitous motif in archaeal and eucaryal transcription. Protein Sci, 2000,9(9): 1743-1752.
28. Ha I, Roberts S, Maldonado E, et al. Multiple functional domains of human transcription factor IIB: distinct interactions with two general transcription factors and RNA polymerase II. Genes Dev, 1993,7(6):1021-1032.
29. Pardee TS, Bangur CS, Ponticelli AS. The N-terminal region of yeast TFIIB contains two adjacent functional domains involved in stable RNA polymerase II binding and transcriptional start site selection. J Biol Chem, 1998,273(28):17859-17864.
30. Miller J, McLachlan AD, Klug A. Repetitive zinc-binding domains in the protein transcription factorⅢA from Xenopus oocytes. EMBO J, 1985,4(6):1609-1614.
31. Evans RM, Hollenberg SM. Zinc finger: Gilt by association. Cell, 1988,52(1):1-3.
32. Liao XB, Clemens KR, Tennant L, et al. Specific interaction of the first three zinc fingers of TFⅢA with the internal control region of the Xenopus 5S RNA gene. J Mol Biol, 1992,223(20):857-871.
33. Shi YG, Berg JM. Specific DNA-RNA hybrid binding by zinc finger proteins. Science, 1995,268(14):282-284.
34. Lee JS, Galvin KM, Shi Y. Evidence for physical interaction between the zinc-finger transcription factors YY1 and Sp11. Proc Natl Acad Sci USA, 1993,90(13):6145-6149.
35. Krishna SS, Majumda I, Grishin NV. Structural classification of zinc fingers. Nucleic Acids Research, 2003,31(2):532-550.
36.孙燕,苟德明,李文鑫. C2H2型锌指蛋白研究进展.生命的化学, 2001,6(21): 473-475.
37. Somers WS, Phillips SE. Crystal structure of the met repressor-operator complex at 2.8 A resolution reveals DNA recognition by beta-strands. Nature, 1992,359(6394): 387-393.
38. Nikolov DB, Hu SH, Lin J, et al. Crystal structure of TFIID TATA-box binding protein. Nature, 1992,360(6399):40-46.
39. Grishin NV. C-terminal domains of Escherichia coli topoisomerase I belong to the zinc-ribbon superfamily. J Mol Biol, 2000,299(5):1165-1177.
40. Jeon C, Yoon H, Agarwal K. The transcription factor TFIIS zinc ribbon dipeptide Asp-Glu is critical for stimulation of elongation and RNA cleavage by RNApolymerase II. Proc Natl Acad Sci, 1994,91(19):9106-9110.
41. Yoon H, Sitikov AS, Jeon C, et al. Preferential interaction of the mRNA proofreading factor TFIIS zinc ribbon with rU.dA base pairs correlates with its function. Biochemistry, 1998,37(35):12104-12112.
42. Wang B, Jones DN, Kaine BP, et al. High-resolution structure of an archaeal zinc ribbon defines a general architectural motif in eukaryotic RNA polymerases. Structure, 1998,6(5):555-569.
43. Hemming SA, Jansma DB, Macgregor PF, et al. RNA polymerase II subunit Rpb9 regulates transcription elongation in vivo. J Biol Chem, 2000,275(45):35506-35511.
44. Spakovskii GV, Lebedenko EN. Molecular identification and characteristics of hRPC11, the smallest specific subunit of human RNA polymerase III. Bioorg Khim, 1998,24(11):877-880.
45. Cabart P, Murphy S. Assembly of human small nuclear RNA gene-specific transcription factor IIIB complex de novo on and off promoter. J Biol Chem, 2002,277(30): 26831-26838.
46. Hong L, Han Y, Shi R, et al. ZNRD1 gene suppresses cell proliferation through cell Cycle arrest in G1 phase. Cancer Biol Ther, 2005,4(1):60-64.
47. Hong L, Han Y, Han Y, et al. Mechanisms of growth arrest by zinc ribbon domain-containing 1 (ZNRD1) in gastric cancer cells. Carcinogenesis, 2007, 28(8):1622-1628.
48. Hayes JD, Wolf CR. Molecular mechanisms of drug resistance. Biochem J, 1990,272(2):281-295.
49. Arceci RJ. Clinical significance of P-Glycoprotein in multidrug resistance malignancies. Blood, 1993,81(9):2215-2222.
50. Gottesman MM, Hrycyna CA. Genetic analysis of the multidrug transporter. Annu Rev Genet, 1995,29:607-649.
51. McCoy C, McGee SB, Cornwell MM. The Wilms' tumor suppressor, WTl,imhibits 120 tetradecanoylphirbol 13 acetate activation of the multidrug resistance 1 promoter. Cell Growth Differ, 1999,10(6):377-386.
52. Bartsevich VV, Juliano RL. Regulation of the MDR1 gene by transcriptional repressors selected using peptide combinatorial libraries. Mol Pharmacol, 2000,58(1):1-10.
53. Hong L, Piao Y, Han Y, et al. Zinc ribbon domain-containing 1 (ZNRD1) mediates multidrug resistance of leukemia cells through regulation of P-glycoprotein and Bcl-2. Mol Cancer Ther, 2005,4(12):1936-1942.
54.张宇梅,赵燕秋,严泉剑,等.锌带基因ZNRD1在胃癌耐药细胞中的表达和功能.中华肿瘤杂志, 2003,25(2):125-129.
55.张宇梅,时永全,金晓航,等. ZNRD1的抗体制备及在胃癌耐药细胞的蛋白表达.中国免疫学杂志, 2003,19(05):325-327.
56. Shi Y, Zhang Y, Zhao Y, et al. Overexpression of ZNRDl promotes multidrug-resistant phenotype of gastric cancer cells through upregulation of P-glycoprotein. Cancer Biol Ther, 2004,3(4):377-381.
57. Hong L, Wang J, Han Y, et al. Reversal of multidrug resistance of vincristine-resistant gastric adenocarcinoma cells through up-regulation of DARPP-32. Cell Biol Int, 2007,31(9):1010-1015.
58. Bartsevich VV, Iuliano RL. Regulation of the MDR1 gene by transcriptional repressors selected using peptide combinatorial libraries. Mol Pharmacol, 2000,58(1):1-10.
59. Ai J, Zhang Z, Xin D, et al. Identification of over-expressed genes in human renal cell carcinoma by combining suppression subtractive hybridization and cDNA library array. Sci China C Life Sci, 2004,47(2):148-157.
60. Kumar A, Chatopadhyay T, Raziuddin M, et al. Discovery of deregulation of zinc homeostasis and its associated genes in esophageal squamous cell carcinoma using cDNA microarray. Int J Cancer, 2007,120(2):230-242.
61. Hong L, Zhang Y, Han S, et al. Preparation and characterization of a novel monoclonal antibody specific to human ZNRD1 protein. Hybrid Hybridomics, 2004,23(l):65-68.
62.赵晓红,郭新宁,翟惠虹,等. ZNRD1在肝癌中的表达及对HepG2细胞增殖的影响.中国肿瘤, 2005,14(1):53-55.
63.艾军魁,张志文,辛殿棋,等.抑制消减杂交结合cDNA微阵列技术鉴定人肾癌组织高表达基因谱.中国科学C辑, 2003,33(5):436-445.
1. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin, 2005,55(2):74-108.
2. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med, 2003,349(23):2241-2252.
3. Yang CS. Research on esophageal cancer in China. Cancer Res, 1980,40(8 Pt 1):2633-2644.
4. van Rensburg SJ. Epidemiologic and dietary evidence for a specific nutritional predisposition to esophageal cancer. J Natl Cancer Inst, 1981,67(2):243-251.
5. Abnet CC, Lai B, Qiao YL, et al. Zinc concentration in esophageal biopsy specimens measured by X-ray fluorescence and esophageal cancer risk. J Natl Cancer Inst, 2005,97(4):301-306.
6. Mu?oz N, Crespi M, Grassi A, et al. Precursor lesions of oesophageal cancer in high-risk populations in Iran and China. Lancet, 1982,17(1):876-879.
7. Sky Peck HH. Trace metals and neoplasia. Clin Physiol Biochem, 1986,4(1):99-111.
8. Vallee BL, Falchuk KH. The biochemical basis of zinc physiology. Physiol-Rev, 1993,73(1):79-118.
9. Fong LY, Sivak A, Newberne PM. Zinc deficiency and methylbenzylnitrosamine- induced esophageal cancer in rats. J Natl Cancer Inst, 1978,61(1):145-150.
10. Fong LY, Li JX, Farber JL, et al. Cell proliferation and esophageal carcinogenesis in the zinc-deficient rat. Carcinogenesis, 1996,17(9):1841-1848.
11. Fong LY, Ishii H, Nguyen VT, et al. p53 deficiency accelerates induction and progression of esophageal and forestomach tumors in zinc-deficient mice. Cancer Res, 2003,63(1):186-195.
12. Lipman TO, Diamond A, Mellow MH, et al. Esophageal zinc content in human squamous esophageal cancer. J Am Coll Nutr, 1987,6(1):41-46.
13. Kumar A, Chatopadhyay T, Raziuddin M, et al. Discovery of deregulation of zinc homeostasis and its associated genes in esophageal squamous cell carcinoma using cDNA microarray. Int J Cancer, 2007,120(2):230-242.
14. Varmeh-Ziaie S, Ichimura K, Yang F, et al. Cloning and chromosomal localization of human WIG-1/PAG608 and demonstration of amplification with increased expressionin primary squamous cell carcinoma of the lung. Cancer Lett, 2001,174(2):179-187.
15. Méndez Vidal C, Prahl M, Wiman KG. The p53-induced Wig-1 protein binds double-stranded RNAs with structural characteristics of siRNAs and miRNAs. FEBS Lett, 2006,580(18):4401-4408.
16. Hellborg F, Wiman KG. The p53-induced Wig-1 zinc finger protein is highly conserved from fish to man. Int J Oncol, 2004,24(6):1559-1564.
17. Brass N, Racz A, Heckel D, et al. Amplification of the genes BCHE and SLC2A2 in 40% of squamous cell carcinoma of the lung. Cancer Res, 1997,57(11):2290-2294.
18. Sattler HP, Lensch R, Rohde V, et al. Novel amplification unit at chromosome 3q25-q27 in human prostate cancer. Prostate, 2000,45(3):207-215.
19. Lazo PA. The molecular genetics of cervical carcinoma. Br J Cancer, 1999, 80(12):2008-2018.
20. Hibi K, Trink B, Patturajan M, et al. AIS is an oncogene amplified in squamous cell carcinoma. Proc Natl Acad Sci USA, 2000,97(10):5462-5467.
21. Sugita M, Tanaka N, Davidson S, et al. Molecular definition of a small amplification domain within 3q26 in tumors of cervix, ovary, and lung, Cancer Genet. Cytogenet, 2000,117(1):9-18.
22. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell, 1997, 88(3):323-331.
23. Lane DP. Cancer. p53, guardian of the genome. Nature, 1992,358(6381):15-16.
24. Hollstein M, Sidransky D, Vogelstein B, et al. p53 mutations in human cancers. Science, 1991,253(5015):49-53.
25. Bedwal RS, Bahuguna A. Zinc, copper and selenium in reproduction. Experientia, 1994,50(7):626-640.
26. Pavletich NP, Chambers KA, Pabo CO. The DNA-binding domain of p53 contains the four conserved regions and the major mutation hot spots. Genes Dev, 1993, 7(12B):2556-2564.
27. Ho E, Ames BN. Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFkappaB and AP1 binding and affects DNA repair in a rat glioma cell line. Proc Natl Acad Sci U S A, 2002,99(26):16770-16775.
28. Fritz G. Human APE/Ref-1 protein. Int J Biochem Cell Biol, 2000,32(9):925-929.
29. Evans AR, Limp-Foster M, Kelley MR. Going APE over ref-1. Mutat Res, 2000,461(2):83-108.
30. Fraker PJ, Jardieu P, Cook J. Zinc deficiency and immune function. Arch Dermatol, 1987,123(12):1699-1701.
31. Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol, 1994,10:405-455.
32. Shaulian E, Karin M. AP-1 in cell proliferation and survival. Oncogene, 2001,20(19):2390-2400.
33. Hennig B, Meerarani P, Ramadass P, et al. Zinc nutrition and apoptosis of vascular endothelial cells: implications in atherosclerosis. Nutrition, 1999,15(10):744-748.
34. Truong-Tran AQ, Carter J, Ruffin RE, et al. The role of zinc in caspase activation and apoptotic cell death. Biometals, 2001,14(3-4):315-330.
35. Nakatani T, Tawaramoto M, Opare Kennedy D, et al. Apoptosis induced by chelation of intracellular zinc is associated with depletion of cellular reduced glutathione level in rat hepatocytes. Chem Biol Interact, 2000,125(3):151-163.
36. Oteiza PI, Clegg MS, Keen CL. Short-term zinc deficiency affects nuclear factor-kappab nuclear binding activity in rat testes. J Nutr, 2001,131(1):21-26.
37. Ho E. Zinc deficiency, DNA damage and cancer risk. J Nutr Biochem, 2004, 15(10):572-578.
38. Federico A, Iodice P, Federico P, et al. Effects of selenium and zinc supplementation on nutritional status in patients with cancer of digestive tract. Eur J Clin Nutr, 2001,55(4):293-297.
39. Prasad AS, Beck FW, Doerr TD, et al. Nutritional and zinc status of head and neck cancer patients: an interpretive review. J Am Coll Nutr, 1998,17(5):409-418.
40. Oteiza PI, Clegg MS, Zago MP, et al. Zinc deficiency induces oxidative stress and AP-1 activation in 3T3 cells. Free Radic Biol Med, 2000,28(7):1091-1099.
41. Golub MS, Gershwin ME, Hurley LS, et al. Studies of marginal zinc deprivation in rhesus monkeys: infant behavior. Am J Clin Nutr, 1985,42(6):1229-1239.
42. Fong LY, Lau KM, Huebner K, et al. Induction of esophageal tumors in zinc-deficient rats by single low doses of N-nitrosomethyl-benzylamine (NMBA): analysis of cell proliferation, and mutations in H-ras and p53 genes. Carcinogenesis, 1997,18(8):1477-1484.
43. Fong LY, Magee PN. Dietary zinc deficiency enhances esophageal cell proliferation and N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumor incidence in C57BL/6 mouse. Cancer Lett, 1999,143(1):63-69.
44. Newberne PM, Schrager TF, Broitman S. Esophageal carcinogenesis in the rat: zinc deficiency and alcohol effects on tumor induction. Pathobiology, 1997,65(1):39-45.
45. Oteiza PI, Olin KL, Fraga CG, et al. Zinc deficiency causes oxidative damage to proteins, lipids and DNA in rat testes. J Nutr, 1995,125(4):823-829.
46. Costello LC, Franklin RB. Novel role of zinc in the regulation of prostate citrate metabolism and its implications in prostate cancer. Prostate, 1998,35(4):285-296.
47. Costello LC, Franklin RB. The intermediary metabolism of the prostate: a key to understanding the pathogenesis and progression of prostate malignancy. Oncology, 2000,59(4):269-282.
48. Kristal AR, Stanford JL, Cohen JH, et al. Vitamin and mineral supplement use is associated with reduced risk of prostate cancer. Cancer Epidemiol Biomarkers Prev, 1999,8(10):887-892.
49. Lu H, Cai L, Mu LN, et al. Dietary mineral and trace element intake and squamous cell carcinoma of the esophagus in a Chinese population. Nutr Cancer, 2006,55(1):63-70.
50. John DH, David AC. Role of Integrins in Cell Invasion and Migration. Nat Cancer Rev, 2002,2(2):91-100.
51. Oue N, Aung PP, Mitani Y, et al. Genes involved in invasion and metastasis of gastric cancer identified by array-based hybridization and serial analysis of gene expression. Oncology, 2005,69(Suppl 1):17-22.
52. Israeli D, Tessler E, Haupt Y, et al. A novel p53-inducible gene, PAG608, encodes a nuclear zinc finger protein whose overexpression promotes apoptosis. EMBO J, 1997,16(14):4384-4392.
53. Varmeh-Ziaie S, Okan I, Wang Y, et al. Wig-1, a new p53-induced gene encoding a zinc finger protein. Oncogene, 1997,15(22):2699-2704.
54. Wilhelm MT, Méndez-Vidal C, Wiman KG. Identification of functional p53-binding motifs in the mouse wig-1 promoter. FEBS Lett, 2002,524(1-3):69-72.