人食管癌表达下调基因的克隆及其结构分析
摘要
食管癌是人类常见恶性肿瘤之一，其发病率位居我国恶性肿瘤发生的第四位。我国是食管癌高发区，世界上一半以上的食管癌发生在我国。食管癌遗传流行学调查显示遗传因素在食管癌发生中起着重要的作用。但是，至今尚未发现食管癌的易感基因，食管上皮的癌变分子机理仍未明确。当前肿瘤分子遗传学的研究重点已逐渐向基因表达研究转变，即从着重质(结构)的改变转向质和量(表达)的改变并重。研究基因表达的外遗传学(epigenetics)亦己成为目前肿瘤分子遗传学研究的一个重要内容。其中，肿瘤表达下调基因分离是筛选侯选肿瘤抑制基因的一个有效途径而倍受重视。目前，国内外对食管癌表达下调基因了解甚少。鉴别和克隆更多的食管癌表达下调基因并了解其在不同个体食管癌组织与正常食管粘膜的基因表达差异状况，不仅可以加强对食管癌发生发展分子机制的阐明，而且有助于食管癌的早期诊断、有针对性的个体治疗以及设计新的抗食管癌药物。
1．应用改进的uRNA差异显示技术分离食管癌组织表达下调cDNA片段
本文首次应用三条锚定引物等摩尔混合物(GT_(15)N，N代表A，G和C)进行mRNA差异显示。采用40个10-mer随机引物(OPA-1至OPA-20，OPB-1至OPB-20)与3条锚定引物的等摩尔混和物(GT_(15)N，N为A，G和C)组合，共获得同时在三对人食管癌组织中均不表达或低表达而在同一病人癌旁食管粘膜都高表达的差异表达带30个。经Northern杂交和PCR分析证实，我们已获得在食管癌组织中表达下调的基因9个，其中有4个是新基因片段。本文主要介绍其中的三个即已知基因Ma1和新基因DRC1和DRC2。本文结果显示此方法重复性较好而且可以加快筛选差异表达基因的速度。
2．两个食管癌表达下调新基因DRC1和DRG2全长cDNA的分离和克隆
应用Marathon RACE技术，以食管癌旁cDNA为模板，分别经过两次和三次RACE反应扩增出DRC1和DRC2基因的5'cDNA末端，从而拼接得到新基因DRC1和DRC2初步的全长cDNA。最后，应用PCR技术从胎儿食管cDNA扩增而得到新基因DRC1和DRC2的全长cDNA。DRC1基因全长cDNA具有51bp
Esophageal cancer (EC), one of the common human malignancies, is the fourth cause of cancer death in China. Our country has much higher incidence than the other areas and accounts for over half of the total esophageal cancer patients in the world. Previous studies on genetic epidemiology have showed that genetic factors may play an important role in the development of esophageal cancer. However, the susceptibility gene(s) of esophageal cancer has not been identified so far. The molecular mechanisms of the development of esophageal cancer are unclear yet. Molecular genetics of cancer is now shifting from focusing on studying DNA mutations to investigating heredity at both DNA and RNA levels. Cancer epigenetics, an approach to studying heredity of gene expression, comes of age. One focus of cancer research has been on the propensities of tumor suppressors to become loss of expression or down-regulation as a function of tumor initiation and progression. It is important to identify the tumor-associated genes which are down-regulated in tumors. Few down-regulated genes in esophageal cancer have been isolated to date. Cloning of more down-regulated genes and analysis of their expression difference between esophageal cancer tissues and normal esophageal mucosa will be invaluable in furthering our understanding of the molecular events that underlie esophageal cancer development, and in producing more new diagnostic, prognostic and therapeutic targets.
1. Isolation of down-regulated genes in human esophageal cancer tissues by using a modified mRNA differential display technique
A modified differential display PCR (DD-PCR) was developed by using a mixture of dT_(15)A, dT_(15)G and dT_(15)C rather than the conventional single anchored primer, to identify down-regulated genes in human esophageal cancer tissues.
1．应用改进的uRNA差异显示技术分离食管癌组织表达下调cDNA片段
本文首次应用三条锚定引物等摩尔混合物(GT_(15)N，N代表A，G和C)进行mRNA差异显示。采用40个10-mer随机引物(OPA-1至OPA-20，OPB-1至OPB-20)与3条锚定引物的等摩尔混和物(GT_(15)N，N为A，G和C)组合，共获得同时在三对人食管癌组织中均不表达或低表达而在同一病人癌旁食管粘膜都高表达的差异表达带30个。经Northern杂交和PCR分析证实，我们已获得在食管癌组织中表达下调的基因9个，其中有4个是新基因片段。本文主要介绍其中的三个即已知基因Ma1和新基因DRC1和DRC2。本文结果显示此方法重复性较好而且可以加快筛选差异表达基因的速度。
2．两个食管癌表达下调新基因DRC1和DRG2全长cDNA的分离和克隆
应用Marathon RACE技术，以食管癌旁cDNA为模板，分别经过两次和三次RACE反应扩增出DRC1和DRC2基因的5'cDNA末端，从而拼接得到新基因DRC1和DRC2初步的全长cDNA。最后，应用PCR技术从胎儿食管cDNA扩增而得到新基因DRC1和DRC2的全长cDNA。DRC1基因全长cDNA具有51bp
Esophageal cancer (EC), one of the common human malignancies, is the fourth cause of cancer death in China. Our country has much higher incidence than the other areas and accounts for over half of the total esophageal cancer patients in the world. Previous studies on genetic epidemiology have showed that genetic factors may play an important role in the development of esophageal cancer. However, the susceptibility gene(s) of esophageal cancer has not been identified so far. The molecular mechanisms of the development of esophageal cancer are unclear yet. Molecular genetics of cancer is now shifting from focusing on studying DNA mutations to investigating heredity at both DNA and RNA levels. Cancer epigenetics, an approach to studying heredity of gene expression, comes of age. One focus of cancer research has been on the propensities of tumor suppressors to become loss of expression or down-regulation as a function of tumor initiation and progression. It is important to identify the tumor-associated genes which are down-regulated in tumors. Few down-regulated genes in esophageal cancer have been isolated to date. Cloning of more down-regulated genes and analysis of their expression difference between esophageal cancer tissues and normal esophageal mucosa will be invaluable in furthering our understanding of the molecular events that underlie esophageal cancer development, and in producing more new diagnostic, prognostic and therapeutic targets.
1. Isolation of down-regulated genes in human esophageal cancer tissues by using a modified mRNA differential display technique
A modified differential display PCR (DD-PCR) was developed by using a mixture of dT_(15)A, dT_(15)G and dT_(15)C rather than the conventional single anchored primer, to identify down-regulated genes in human esophageal cancer tissues.
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