Basic Strategy for the treatment of kidney cancer : identification and clinical utilization of new tumor suppressor genes or oncogenes closely correlated with VHL gene VHL

第一个目的是利用基因芯片从肾癌细胞中寻找生长因子蛋白。基于这一观点，我们与东京大学医学科学研究所的人类基因组中心合作。我们鉴定了一种癌胚蛋白质，仅在人肾癌细胞中表达，而在其他器官中不表达，并分泌到血流中。此外，我们还鉴定了另外3种候选蛋白。HIG2是一个增长因子。它是一种分泌蛋白。由于其抗体抑制肾癌细胞的生长，因此可以控制人类肾癌的增殖。由于它在人肾癌患者的血液中被检测到，因此预期它在未来作为人肾癌的肿瘤标记物是有用的。目前，这一想法正在审查中。第二个目的是鉴定在人肾癌中特异性甲基化的基因，该基因具有VHL基因突变。甲基化的基因作为肿瘤抑制基因发挥作用，如 关于我们 e VHL。这些基因还没有被发现。据阐明，RASSF1A在40%的肾细胞癌中甲基化。我们与札幌医学院的丰田实博士合作，对人类肾癌中的甲基化基因进行了筛查。我们鉴定了甲基化的岛，MIRC-1、MIRC-2、MIRC-3和MIRC-4。通过对MIRC-1基因的分析，确定MIRC-1基因为同源异型盒基因HOXB 13。结果表明，该蛋白仅在肾脏近端小管中表达。当其高度表达时，其诱导人肾细胞癌中的细胞凋亡。在人类肾癌中，Hoxb13的甲基化频率为30%。对该基因在基因治疗中的应用前景进行了展望。此外，它还可用作血液和尿液中的肿瘤标志物，并使用该基因中的甲基化。我们试图确定3个甲基化岛的负责基因。第三个目的是与东京医科齿科大学的稻泽丈二博士合作进行人类肾癌的DNA比较基因组杂交或CGH微阵列研究。在30个肾癌细胞系中鉴定特异性缺失的DNA片段并不成功。少

The first purpose is to search the growth factor protein using microarray from kidney cancer cells. With this viewpoint we collaborated with Human Genome Center in the Medical Science Institute, University of Tokyo. We identified HIG2, an oncofetal protein, that is expressed only human kidney cancer cells but not in other organ, which is secreted into blood stream. In addition we identified 3 more candidacy proteins. HIG2 works as a growth factor. It is a secretary protein. Since its antibody suppresses the growth of kidney cancer cells, it can control the multiplication of the human kidney cancer. As it is detected in the blood of the human kidney cancer patient, its usefulness is expected as a tumor marker for the human kidney cancers in the future. Presently this idea is the under examination. The 2nd purpose is to identify the gene that is specifically methylated in human kidney cancers, which has VHL gene mutation. The genes that are methylated works as tumor suppressor genes, lik … More e VHL. These genes are not identified yet. It is elucidated that RASSF1A is methylated in 40% kidney cell cancers. We collaborated with Dr.Minoru Toyota, Sapporo Medical School, for the screening of methylated genes in human kidney cancer. We identified methylated islands, MIRC-1, MIRC-2, MIRC-3 and MIRC-4. With the analyses of MIRC-1, we conformed MIRC-1 as a Homeobox gene, HOXB13. It is revealed this protein is expressed only in the proximal tubules in the kidney. When it is highly expressed, it induces apoptosis in the human kidney cell cancer. Methylation frequency in Hoxb13 is 30% in human kidney cancers. It is expected the application of this gene for gene therapy in the future. In addition it is also applicable as a tumor marker in the blood and the urine with use of methylation in this gene. We try to identify the responsible genes for 3 more methylated islands. The 3rd purpose is DNA comparative genomic hybridization or CGH microarray study for human kidney cancers in collaboration with Dr.Joji Inazawa at the Tokyo Medical and Dental College. The identification of the specifically deleted DNA portion in human kidney cancers was not successful difficult in 30 cell lines. Less