Identification of the transcription factor single-minded homologue 2 as a potential biomarker and immunotherapy target in prostate cancer.
Identification of the transcription factor single-minded homologue 2 as a potential biomarker and immunotherapy target in prostate cancer.
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将转录因子识别为单一的同源物2作为前列腺癌中潜在的生物标志物和免疫疗法靶标。
DOI：
10.1158/1078-0432.ccr-09-0911
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发表时间：
2009-09-15
期刊：
影响因子：
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通讯作者：
Sanda MG
中科院分区：
文献类型：
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作者：
Arredouani MS;Lu B;Bhasin M;Eljanne M;Yue W;Mosquera JM;Bubley GJ;Li V;Rubin MA;Libermann TA;Sanda MG
鉴别前列腺癌（PCa）新的生物标志物和免疫治疗靶点对更好的诊断和治疗至关重要。我们试图鉴定新的前列腺癌肿瘤相关抗原（TAA），这些抗原在前列腺癌中表达，在非前列腺组织中缺失，并且对人类HLA限制的免疫反应具有免疫原性。通过对正常和癌性人前列腺组织的微阵列分析，我们发现了1063个在前列腺癌中过表达的基因。在公开可用的阵列数据集中验证了195个转录本后，我们询问了这些TAA在正常人体组织中的表达，以鉴定在正常、非前列腺成人组织中未表达到可检测水平的基因。我们确定了23个PCa TAA候选者。RT-PCR证实其中15个基因在前列腺癌中过表达（P <0.05）。最常见的过表达基因SIM2 （single-minded homolog 2）被选择作为免疫治疗的潜在靶点进行进一步评估。ELISA检测显示，部分PCa患者血清中存在SIM2自身抗体，显示出对SIM2的免疫反应。接下来，我们发现推定的hla -A2.1限制性SIM2表位与人A2.1结合，并且转基因HLA2.1小鼠的免疫在体内诱导了SIM2特异性CTL反应。我们发现SIM2在前列腺癌中选择性表达；人类HLA a2.1限制性SIM2表位在体内诱导特异性T细胞，并且在前列腺癌患者血清中检测到抗SIM2抗体，这表明SIM2是前列腺癌相关抗原，是前列腺癌免疫治疗的合适潜在靶点。
Identification of novel biomarkers and immunotherapy targets for prostate cancer (PCa) is crucial to better diagnosis and therapy. We sought to identify novel prostate cancer tumor-associated antigens (TAA) that are expressed in prostate cancer, absent in non-prostate human tissue, and immunogenic for immune responses restricted by human HLA. Using microarray analysis of normal and cancerous human prostate tissues, we identified 1063 genes over-expressed in PCa. After validating 195 transcripts in publicly available array datasets, we interrogated expression of these TAA in normal human tissues to identify genes that are not expressed at detectable levels in normal, non-prostate adult human tissue. We identified 23 PCa TAA candidates. RT-PCR confirmed that 15 of these genes were over-expressed in prostate cancer (P <0.05 for each). The most frequently over-expressed gene, SIM2 (single-minded homolog 2), was selected for further evaluation as a potential target for immunotherapy. ELISA assay revealed that a fraction of PCa patients exhibited immune responsiveness to SIM2 as evidenced by the presence of auto-antibodies to SIM2 in their sera. We next showed binding of putative HLA-A2.1-restricted SIM2 epitopes to human A2.1, and immunization of transgenic HLA2.1 mice showed induction of SIM2-specific CTL responses in vivo. Our findings that SIM2 is selectively expressed in prostate cancer; that human HLA A2.1-restricted SIM2 epitopes induce specific T cells in vivo, and that anti-SIM2 antibodies are detectable in PCa patients’ sera, implicate SIM2 as a prostate cancer-associated antigen that is a suitable potential target for prostate cancer immunotherapy.