区分侵袭性和惰性前列腺癌的蛋白质特征。
Protein signatures to distinguish aggressive from indolent prostate cancer.
机构信息
Department of Radiology, Stanford University School of Medicine, Canary Center at Stanford for Cancer Early Detection, Palo Alto, California, USA.
Department of Urology, Stanford University School of Medicine, Stanford, Calilfornia, USA.
出版信息
Prostate. 2022 Apr;82(5):605-616. doi: 10.1002/pros.24307. Epub 2022 Jan 31.
BACKGROUND
Distinguishing men with aggressive from indolent prostate cancer is critical to decisions in the management of clinically localized prostate cancer. Molecular signatures of aggressive disease could help men overcome this major clinical challenge by reducing unnecessary treatment and allowing more appropriate treatment of aggressive disease.
METHODS
We performed a mass spectrometry-based proteomic analysis of normal and malignant prostate tissues from 22 men who underwent surgery for prostate cancer. Prostate cancer samples included Grade Groups (3-5), with 8 patients experiencing recurrence and 14 without evidence of recurrence with a mean of 6.8 years of follow-up. To better understand the biological pathways underlying prostate cancer aggressiveness, we performed a systems biology analysis and gene enrichment analysis. Proteins that distinguished recurrent from nonrecurrent cancer were chosen for validation by immunohistochemical analysis on tissue microarrays containing samples from a larger cohort of patients with recurrent and nonrecurrent prostate cancer.
RESULTS
In all, 24,037 unique peptides (false discovery rate < 1%) corresponding to 3,313 distinct proteins were identified with absolute abundance ranges spanning seven orders of magnitude. Of these proteins, 115 showed significantly (p < 0.01) different levels in tissues from recurrent versus nonrecurrent cancers. Analysis of all differentially expressed proteins in recurrent and nonrecurrent cases identified several protein networks, most prominently one in which approximately 24% of the proteins in the network were regulated by the YY1 transcription factor (adjusted p < 0.001). Strong immunohistochemical staining levels of three differentially expressed proteins, POSTN, CALR, and CTSD, on a tissue microarray validated their association with shorter patient survival.
CONCLUSIONS
The protein signatures identified could improve understanding of the molecular drivers of aggressive prostate cancer and be used as candidate prognostic biomarkers.
背景
区分侵袭性和惰性前列腺癌对临床局限性前列腺癌的治疗决策至关重要。侵袭性疾病的分子特征可以通过减少不必要的治疗和允许更适当的侵袭性疾病治疗来帮助男性克服这一主要临床挑战。
方法
我们对 22 名因前列腺癌接受手术的男性的正常和恶性前列腺组织进行了基于质谱的蛋白质组学分析。前列腺癌样本包括分级组（3-5 级），其中 8 例有复发，14 例无复发证据，平均随访 6.8 年。为了更好地了解前列腺癌侵袭性的生物学途径，我们进行了系统生物学分析和基因富集分析。选择区分复发和非复发癌症的蛋白质进行验证，方法是对包含复发和非复发前列腺癌患者更大队列样本的组织微阵列进行免疫组织化学分析。
结果
总共鉴定出 24037 个独特肽（错误发现率<1%），对应于 3313 种不同的蛋白质，绝对丰度范围跨越七个数量级。在复发与非复发肿瘤组织中，有 115 种蛋白质的表达水平差异有统计学意义（p<0.01）。对复发和非复发病例中所有差异表达蛋白质的分析确定了几个蛋白质网络，其中最突出的一个网络中约 24%的蛋白质受到 YY1 转录因子的调节（调整后 p<0.001）。在组织微阵列上对三个差异表达蛋白质 POSTN、CALR 和 CTSD 的强烈免疫组织化学染色水平验证了它们与患者生存时间较短的关联。
结论
鉴定出的蛋白质特征可以提高对侵袭性前列腺癌分子驱动因素的理解，并可作为候选预后生物标志物。
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