Proteomic characterization of primary and metastatic prostate cancer reveals reduced proteinase activity in aggressive tumors

Abstract Prostate cancer (PCa) is a heterogeneous group of tumors with variable clinical courses. In order to improve patient outcomes, it is critical to clinically separate aggressive PCa (AG) from non-aggressive PCa (NAG). Although recent genomic studies have identified a spectrum of molecular abn...

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Autores principales:	Qing Kay Li, Jing Chen, Yingwei Hu, Naseruddin Höti, Tung-Shing Mamie Lih, Stefani N. Thomas, Li Chen, Sujayita Roy, Alan Meeker, Punit Shah, Lijun Chen, G. Steven Bova, Bai Zhang, Hui Zhang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/eec67f5b900a4b039dc046a5f2d3d03b
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spelling	oai:doaj.org-article:eec67f5b900a4b039dc046a5f2d3d03b2021-12-02T17:26:49ZProteomic characterization of primary and metastatic prostate cancer reveals reduced proteinase activity in aggressive tumors10.1038/s41598-021-98410-02045-2322https://doaj.org/article/eec67f5b900a4b039dc046a5f2d3d03b2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98410-0https://doaj.org/toc/2045-2322Abstract Prostate cancer (PCa) is a heterogeneous group of tumors with variable clinical courses. In order to improve patient outcomes, it is critical to clinically separate aggressive PCa (AG) from non-aggressive PCa (NAG). Although recent genomic studies have identified a spectrum of molecular abnormalities associated with aggressive PCa, it is still challenging to separate AG from NAG. To better understand the functional consequences of PCa progression and the unique features of the AG subtype, we studied the proteomic signatures of primary AG, NAG and metastatic PCa. 39 PCa and 10 benign prostate controls in a discovery cohort and 57 PCa in a validation cohort were analyzed using a data-independent acquisition (DIA) SWATH–MS platform. Proteins with the highest variances (top 500 proteins) were annotated for the pathway enrichment analysis. Functional analysis of differentially expressed proteins in NAG and AG was performed. Data was further validated using a validation cohort; and was also compared with a TCGA mRNA expression dataset and confirmed by immunohistochemistry (IHC) using PCa tissue microarray (TMA). 4,415 proteins were identified in the tumor and benign control tissues, including 158 up-regulated and 116 down-regulated proteins in AG tumors. A functional analysis of tumor-associated proteins revealed reduced expressions of several proteinases, including dipeptidyl peptidase 4 (DPP4), carboxypeptidase E (CPE) and prostate specific antigen (KLK3) in AG and metastatic PCa. A targeted analysis further identified that the reduced expression of DPP4 was associated with the accumulation of DPP4 substrates and the reduced ratio of DPP4 cleaved peptide to intact substrate peptide. Findings were further validated using an independently-collected tumor cohort, correlated with a TCGA mRNA dataset, and confirmed by immunohistochemical stains of PCa tumor microarray (TMA). Our study is the first large-scale proteomics analysis of PCa tissue using a DIA SWATH-MS platform. It provides not only an interrogative proteomic signature of PCa subtypes, but also indicates the critical roles played by certain proteinases during tumor progression. The spectrum map and protein profile generated in the study can be used to investigate potential biological mechanisms involved in PCa and for the development of a clinical assay to distinguish aggressive from indolent PCa.Qing Kay LiJing ChenYingwei HuNaseruddin HötiTung-Shing Mamie LihStefani N. ThomasLi ChenSujayita RoyAlan MeekerPunit ShahLijun ChenG. Steven BovaBai ZhangHui ZhangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Qing Kay Li Jing Chen Yingwei Hu Naseruddin Höti Tung-Shing Mamie Lih Stefani N. Thomas Li Chen Sujayita Roy Alan Meeker Punit Shah Lijun Chen G. Steven Bova Bai Zhang Hui Zhang Proteomic characterization of primary and metastatic prostate cancer reveals reduced proteinase activity in aggressive tumors
description	Abstract Prostate cancer (PCa) is a heterogeneous group of tumors with variable clinical courses. In order to improve patient outcomes, it is critical to clinically separate aggressive PCa (AG) from non-aggressive PCa (NAG). Although recent genomic studies have identified a spectrum of molecular abnormalities associated with aggressive PCa, it is still challenging to separate AG from NAG. To better understand the functional consequences of PCa progression and the unique features of the AG subtype, we studied the proteomic signatures of primary AG, NAG and metastatic PCa. 39 PCa and 10 benign prostate controls in a discovery cohort and 57 PCa in a validation cohort were analyzed using a data-independent acquisition (DIA) SWATH–MS platform. Proteins with the highest variances (top 500 proteins) were annotated for the pathway enrichment analysis. Functional analysis of differentially expressed proteins in NAG and AG was performed. Data was further validated using a validation cohort; and was also compared with a TCGA mRNA expression dataset and confirmed by immunohistochemistry (IHC) using PCa tissue microarray (TMA). 4,415 proteins were identified in the tumor and benign control tissues, including 158 up-regulated and 116 down-regulated proteins in AG tumors. A functional analysis of tumor-associated proteins revealed reduced expressions of several proteinases, including dipeptidyl peptidase 4 (DPP4), carboxypeptidase E (CPE) and prostate specific antigen (KLK3) in AG and metastatic PCa. A targeted analysis further identified that the reduced expression of DPP4 was associated with the accumulation of DPP4 substrates and the reduced ratio of DPP4 cleaved peptide to intact substrate peptide. Findings were further validated using an independently-collected tumor cohort, correlated with a TCGA mRNA dataset, and confirmed by immunohistochemical stains of PCa tumor microarray (TMA). Our study is the first large-scale proteomics analysis of PCa tissue using a DIA SWATH-MS platform. It provides not only an interrogative proteomic signature of PCa subtypes, but also indicates the critical roles played by certain proteinases during tumor progression. The spectrum map and protein profile generated in the study can be used to investigate potential biological mechanisms involved in PCa and for the development of a clinical assay to distinguish aggressive from indolent PCa.
format	article
author	Qing Kay Li Jing Chen Yingwei Hu Naseruddin Höti Tung-Shing Mamie Lih Stefani N. Thomas Li Chen Sujayita Roy Alan Meeker Punit Shah Lijun Chen G. Steven Bova Bai Zhang Hui Zhang
author_facet	Qing Kay Li Jing Chen Yingwei Hu Naseruddin Höti Tung-Shing Mamie Lih Stefani N. Thomas Li Chen Sujayita Roy Alan Meeker Punit Shah Lijun Chen G. Steven Bova Bai Zhang Hui Zhang
author_sort	Qing Kay Li
title	Proteomic characterization of primary and metastatic prostate cancer reveals reduced proteinase activity in aggressive tumors
title_short	Proteomic characterization of primary and metastatic prostate cancer reveals reduced proteinase activity in aggressive tumors
title_full	Proteomic characterization of primary and metastatic prostate cancer reveals reduced proteinase activity in aggressive tumors
title_fullStr	Proteomic characterization of primary and metastatic prostate cancer reveals reduced proteinase activity in aggressive tumors
title_full_unstemmed	Proteomic characterization of primary and metastatic prostate cancer reveals reduced proteinase activity in aggressive tumors
title_sort	proteomic characterization of primary and metastatic prostate cancer reveals reduced proteinase activity in aggressive tumors
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/eec67f5b900a4b039dc046a5f2d3d03b
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Proteomic characterization of primary and metastatic prostate cancer reveals reduced proteinase activity in aggressive tumors

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