A secreted signature discriminates indolent from aggressive prostate tumors.

IF 2.9 2区 医学 Q2 UROLOGY & NEPHROLOGY
Yu Wang, Yong Liu, Xiaona Lin, Kebing Wang, Haidong Wen, Chutian Xiao, Yisong Guo, Jianjie Wu, Ke Li, Zheng Chen, Yanying Ji, Gengguo Deng, Jinming Di, Xin Gao
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引用次数: 0

Abstract

Background: No non-invasive biomarkers are clinically available to distinguish aggressive prostate cancer (PCa) from the indolent PCa, as thus may lead the misdiagnose and overtreatment to the patients. This study aims to identify secreted proteins and assess their potentials to discriminate two PCa subtypes.

Methods: Microarray assay on tissue specimens of the discovery cohort identified secreted genes associated with invasive PCa and macrophage polarization, and the results were validated in an independent cohort. As elevated expression of ΔC499 has been linked to metastatic PCa and poorer prognosis, the relationship of key secretory genes and ΔC499 was investigated. Their roles on macrophage polarization were studied in co-cultured cells, PCa mouse model and patient blood samples. Finally, a multi-gene secreted signature model was developed and tested in training and validation cohorts.

Results: ITGB5 was upregulated and TIMP1/TMEM176B were downregulated at RNA level in aggressive Pca, with bioinformatics linking these changes to M2 macrophage polarization. Additionally, we found that ITGB5 expression was positively regulated while TIMP1 and TMEM176B were negatively regulated through distinct transcriptional pathways. Further, we revealed that ΔC499 contributes to ITGB5-driven M2 macrophage polarization, enhancing PCa invasion in vitro and in vivo. Lastly, a multi-gene model integrating ITGB5, TIMP1, and TMEM176B distinguished indolent from aggressive PCa in training cohort (AUC = 0.88) and validation cohort (AUC = 0.90).

Conclusion: ΔC499 induces M2 macrophage polarization and drives PCa invasiveness by modulating ITGB5, TIMP1, and TMEM176B. Three genes signature is differentially expressed between aggressive and indolent tumors, providing potential non-invasive biomarkers to discriminate aggressive from indolent PCa.

分泌的特征可以区分惰性前列腺肿瘤和侵袭性前列腺肿瘤。
背景:目前临床上尚无非侵入性生物标志物用于区分侵袭性前列腺癌和惰性前列腺癌,这可能导致患者的误诊和过度治疗。本研究旨在鉴定分泌蛋白并评估其鉴别两种PCa亚型的潜力。方法:对发现队列的组织标本进行微阵列检测,发现与侵袭性前列腺癌和巨噬细胞极化相关的分泌基因,并在独立队列中验证结果。由于ΔC499的高表达与转移性前列腺癌和较差的预后有关,因此研究了关键分泌基因与ΔC499的关系。在共培养细胞、PCa小鼠模型和患者血液样本中研究了它们对巨噬细胞极化的作用。最后,建立了一个多基因分泌的特征模型,并在训练和验证队列中进行了测试。结果:侵袭性Pca中ITGB5在RNA水平上调,TIMP1/TMEM176B下调,生物信息学表明这些变化与M2巨噬细胞极化有关。此外,我们发现ITGB5的表达通过不同的转录途径受到正调控,而TIMP1和TMEM176B的表达受到负调控。此外,我们发现ΔC499有助于itgb5驱动的M2巨噬细胞极化,增强体外和体内PCa的侵袭。最后,整合ITGB5、TIMP1和TMEM176B的多基因模型在训练组(AUC = 0.88)和验证组(AUC = 0.90)中区分了惰性PCa和侵袭性PCa。结论:ΔC499通过调节ITGB5、TIMP1和TMEM176B诱导M2巨噬细胞极化,驱动PCa侵袭。三个基因标记在侵袭性和惰性肿瘤中表达差异,为区分侵袭性和惰性前列腺癌提供了潜在的非侵入性生物标志物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
World Journal of Urology
World Journal of Urology 医学-泌尿学与肾脏学
CiteScore
6.80
自引率
8.80%
发文量
317
审稿时长
4-8 weeks
期刊介绍: The WORLD JOURNAL OF UROLOGY conveys regularly the essential results of urological research and their practical and clinical relevance to a broad audience of urologists in research and clinical practice. In order to guarantee a balanced program, articles are published to reflect the developments in all fields of urology on an internationally advanced level. Each issue treats a main topic in review articles of invited international experts. Free papers are unrelated articles to the main topic.
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