Identification of secernin 1 as a novel immunotherapy target for gastric cancer using the expression profiles of cDNA microarray
Identification of secernin 1 as a novel immunotherapy target for gastric cancer using the expression profiles of cDNA microarray
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DOI：
10.1111/j.1349-7006.2006.00194.x
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发表时间：
2006-05-01
期刊：
影响因子：
5.7
通讯作者：
Tahara, H
中科院分区：
文献类型：
--
作者：
Suda, T;Tsunoda, T;Tahara, H
尽管发现了多种TAA，但只有有限数量可用于临床应用，特别是针对上皮恶性肿瘤。在这项研究中，我们寻找新的TAAs使用表达谱的胃癌检测基因芯片，并确定了SCRN 1基因作为候选人。用半定量RT-PCR方法检测了7例胃癌中5例SCRN 1的表达。用北方印迹分析，它在睾丸和卵巢中被大量检测到，而在其他14个正常成人器官中几乎检测不到。集落形成实验表明，其增强的表达与促进的细胞生长有关。由于SCRN 1的这些表达谱和功能特征似乎与假设的理想TAA的特征相容，我们检查了SCRN 1蛋白是否含有限制于HLA-A*0201的抗原表位肽。我们合成了来源于SCRN 1的候选肽，并尝试用每个肽诱导CTL。用肽SCRN 1 -196（KMDAEHPEL）成功地诱导CTL克隆，并且它们不仅裂解肽脉冲靶，而且裂解内源性表达SCRN 1和HLA-A*0201的肿瘤细胞。这些结果强烈表明SCRN 1 -196是限制于HLA-A*0201的表位肽。此外，我们还合成了一种锚定修饰的肽SCRN 1 -9 V（KMDAEHPEV），其中9位的亮氨酸取代了缬氨酸，以增加与HLA-A*0201分子的结合亲和力。由SCRN 1 -9 V诱导的CTL克隆也识别内源性表达其天然SCRN 1蛋白的肿瘤细胞。这些结果有力地表明，SCRN 1是一种新的TAA，这些肽，无论是天然的还是修饰的，都可能适用于癌症疫苗来治疗胃癌。
Despite the discovery of multiple TAAs, only a limited number is available for clinical application, particularly against epithelial malignancies. In this study we searched for novel TAAs using expression profiles of gastric cancer examined with cDNA microarray, and identified the SCRN1 gene as a candidate. SCRN1 was confirmed to be expressed in five out of seven gastric cancers with semiquantitative RT-PCR. With Northern blot analysis, it was detected abundantly in the testis and ovary, but it was barely detectable in 14 other normal human adult organs. Colony formation assay revealed that its augmented expression is associated with promoted cell growth. As these expression profiles and functional features of SCRN1 appeared to be compatible with the characteristics of the hypothesized ideal TAAs, we examined whether SCRN1 protein contains antigenic epitope peptides restricted to HLA-A*0201. We synthesized the candidate peptides derived from SCRN1, and tried to induce CTLs with each peptide. The CTL clones were successfully induced with a peptide SCRN1-196 (KMDAEHPEL), and they lyzed not only the peptide-pulsed targets but also the tumor cells expressing both SCRN1 and HLA-A*0201 endogenously. These results strongly suggest that SCRN1-196 is an epitope peptide restricted to HLA-A*0201. Furthermore, we synthesized an anchor-modified peptide SCRN1-9 V (KMDAEHPEV), in which leucine at position 9 was substituted for valine to increase the binding affinity to the HLA-A*0201 molecules. The CTL clones induced by SCRN1-9 V also recognized tumor cells expressing its natural SCRN1 protein endogenously. These results strongly suggest that SCRN1 is a novel TAA and these peptides, both native and modified, may be applicable for cancer vaccines to treat gastric cancer.