骨桥蛋白 mRNA 剪接变异体在前列腺癌和良性前列腺增生中的表达分析。

Expression analysis of osteopontin mRNA splice variants in prostate cancer and benign prostatic hyperplasia.

机构信息

Programa de Medicina Experimental, Coordenação de Pesquisa-Instituto Nacional de Câncer, Programa de Pós Graduação Stricto Sensu em Oncologia do INCa, Rio de Janeiro-RJ, Brazil.

出版信息

Exp Mol Pathol. 2012 Feb;92(1):13-9. doi: 10.1016/j.yexmp.2011.09.014. Epub 2011 Sep 22.

DOI:10.1016/j.yexmp.2011.09.014

PMID:21963599

Abstract

Osteopontin splicing isoforms (OPN-SI) present differential expression patterns and specific tumor roles. Our aims were to characterize OPN-SI expression in prostate cancer (PCa) and benign prostate hyperplasia (BPH) tissues, besides evaluating their potential as biomarkers for PCa diagnosis and prognostic implications. Prostatic tissue specimens were obtained from 40 PCa and 30 benign prostate hyperplasia (BPH) patients. Quantitative real time PCR (qRT-PCR) was used to measure OPN-SI mRNA expression. Immunohistochemical analysis was performed using an anti-OPNc polyclonal antibody. Biostatistical analyses evaluated the association of OPN-SI and total Prostate Specific Antigen (PSA) serum levels with clinical and pathological data. PCa tissue samples presented significantly higher levels of OPNa, OPNb and OPNc transcripts (p<0.01) than in BPH specimens. OPN-SI mRNA expression were positively correlated with Gleason Score (p<0.01). ROC curves and logistic regression analyses demonstrated that OPN-SI and PSA were able to distinguish PCa from BPH patients (p<0.01). The OPNc isoform was the most upregulated variant and the best marker to distinguish patients' groups, presenting sensitivity and specificity of 90% and 100%, respectively. Immunohistochemistry analysis also demonstrated OPNc upregulation in PCa samples as compared to BPH tissues. OPNcprotein was also strongly stained PCa tissues presenting High Gleason Score. Multivariate analysis indicated that OPNc expression levels above the cut-off value presented a chance 4-fold higher for PCa occurrence. We conclude that OPN-SI were overexpressed in PCa tissues, strongly associated with PCa occurrence and with tumor cell differentiation. Our results suggest OPNc splicing isoform as an important biomarker contributing to improve PCa diagnosis and prognosis, besides providing insights into early steps of PCa carcinogenesis.

摘要

骨桥蛋白剪接异构体（OPN-SI）表现出不同的表达模式和特定的肿瘤作用。我们的目的是研究前列腺癌（PCa）和良性前列腺增生（BPH）组织中 OPN-SI 的表达特征，并评估其作为 PCa 诊断和预后标志物的潜力。从 40 例 PCa 和 30 例 BPH 患者中获得前列腺组织标本。使用定量实时 PCR（qRT-PCR）测量 OPN-SI mRNA 的表达。使用抗 OPNc 多克隆抗体进行免疫组织化学分析。生物统计学分析评估了 OPN-SI 和总前列腺特异性抗原（PSA）血清水平与临床和病理数据的相关性。PCa 组织样本中的 OPNa、OPNb 和 OPNc 转录物水平明显高于 BPH 标本（p<0.01）。OPN-SI mRNA 表达与 Gleason 评分呈正相关（p<0.01）。ROC 曲线和逻辑回归分析表明，OPN-SI 和 PSA 能够区分 PCa 和 BPH 患者（p<0.01）。OPNc 异构体是上调最明显的变体，也是区分患者组的最佳标志物，其敏感性和特异性分别为 90%和 100%。免疫组织化学分析还表明，与 BPH 组织相比，OPNc 在 PCa 样本中上调。OPNc 蛋白在具有高 Gleason 评分的 PCa 组织中也呈强染色。多变量分析表明，OPNc 表达水平高于临界值时，PCa 发生的机会增加 4 倍。我们的结论是，OPN-SI 在 PCa 组织中过度表达，与 PCa 的发生及其与肿瘤细胞分化强烈相关。我们的结果表明，OPNc 剪接异构体是一种重要的生物标志物，有助于改善 PCa 的诊断和预后，并为 PCa 癌变的早期步骤提供了新的见解。