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
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DOI：
10.1158/0008-5472.can-05-0120
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发表时间：
2005-06-01
期刊：
影响因子：
11.2
通讯作者：
Nakamura, Y
中科院分区：
文献类型：
--
作者：
Togashi, A;Katagiri, T;Nakamura, Y
为了鉴定可用作肾细胞癌 (RCC) 诊断标记物和新型治疗药物靶标的分子，我们使用 cDNA 微阵列研究了 RCC 的全基因组表达谱。我们随后证实缺氧诱导蛋白 2 (HIG2) 仅在肾细胞癌和胎儿肾脏中表达。将 HIG2 cDNA 诱导到 COS7 细胞中，导致基因产物分泌到培养基中，从而促进细胞生长。小干扰RNA有效抑制人RCC细胞中HIG2的表达，这些细胞内源性表达高水平的蛋白质，并显着抑制细胞生长。此外，在培养基中添加多克隆抗HIG2抗体可诱导RCC衍生细胞系凋亡。通过与卷曲同源物 10 (FZD10) 的胞外结构域结合，HIG2 蛋白增强了致癌 Writ 信号传导及其自身转录，表明该产物可能具有自分泌生长因子的功能。对临床样本的 ELISA 分析发现，即使在肿瘤发展的早期阶段，HIG2 蛋白也会分泌到 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明显较低。综合证据表明，该分子是分子靶向治疗开发的有希望的候选者，并且可以作为肾癌患者的重要诊断肿瘤标志物。
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 of HIG2 cDNA 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 of HIG2 in 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 Writ 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.