Hypoxia-inducible protein 2 (HIG2), a novel diagnostic marker for renal cell carcinoma and potential target for molecular therapy.
Hypoxia-inducible protein 2 (HIG2), a novel diagnostic marker for renal cell carcinoma and potential target for molecular therapy.
复制标题
DOI：
10.1016/s0022-5347(05)01030-x
复制
发表时间：
2005-06
期刊：
影响因子：
11.2
通讯作者：
Akira Togashi;T. Katagiri;S. Ashida;T. Fujioka;O. Maruyama;Y. Wakumoto;Y. Sakamoto;M. Fujime;
中科院分区：
文献类型：
--
作者：
Akira Togashi;T. Katagiri;S. Ashida;T. Fujioka;O. Maruyama;Y. Wakumoto;Y. Sakamoto;M. Fujime;
为了确定分子作为肾细胞癌（RCC）的诊断标志物，并作为新的治疗药物的目标，我们研究了全基因组表达谱的RCCs使用cDNA微阵列。我们随后证实，缺氧诱导蛋白-2（HIG 2）只在RCC和胎儿肾脏中表达。在COS 7细胞中导入HIG 2cDNA后，基因产物分泌到培养基中，促进细胞生长。小干扰RNA有效地抑制了内源性高表达该蛋白的人肾细胞癌细胞中HIGH 2的表达，并显著抑制了细胞生长。此外，向培养基中加入多克隆抗-HIG 2抗体诱导RCC衍生细胞系的凋亡。通过与卷曲同源物10（FZD 10）的细胞外结构域结合，HIGH 2蛋白增强致癌Wnt信号传导及其自身的转录，表明该产物可能作为自分泌生长因子起作用。临床样品的ELISA分析鉴定了即使在肿瘤发展的早期阶段，仍有HIGH 2蛋白分泌到RCC患者的血浆中，而在健康志愿者或慢性肾小球肾炎患者中检测到的水平显著较低。综合证据表明，这种分子代表了一个有前途的候选人的分子靶向治疗的发展，并可能作为一个突出的诊断肾癌患者的肿瘤标志物。
To identify molecules to serve as diagnostic markers for renal cell carcinoma (RCC) and as targets for novel therapeutic drugs, we investigated genome-wide expression profiles of RCCs using a cDNA microarray. We subsequently confirmed that hypoxia-inducible protein-2 (HIG2) was expressed exclusively in RCCs and fetal kidney. Induction ofHIG2cDNA into COS7 cells led to secretion of the gene product into culture medium and resulted in enhancement of cell growth. Small interfering RNA effectively inhibited expression ofHIG2in human RCC cells that endogenously expressed high levels of the protein and significantly suppressed cell growth. Moreover, addition of polyclonal anti-HIG2 antibody into culture medium induced apoptosis in RCC-derived cell lines. By binding to an extracellular domain of frizzled homologue 10 (FZD10), HIG2 protein enhanced oncogenic Wnt signaling and its own transcription, suggesting that this product is likely to function as an autocrine growth factor. ELISA analysis of clinical samples identified secretion of HIG2 protein into the plasma of RCC patients even at an early stage of tumor development, whereas it was detected at significantly lower levels in healthy volunteers or patients with chronic glomerulonephritis. The combined evidence suggests that this molecule represents a promising candidate for development of molecular-targeting therapy and could serve as a prominent diagnostic tumor marker for patients with renal carcinomas.