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Alterations of Plasma Exosomal Proteins and Metabolites are Associated with the Progression of Castration-Resistant Prostate Cancer

41 Pages Posted: 23 Mar 2022

See all articles by Pengyu Liu

Pengyu Liu

Southern Medical University - Shenzhen Key Laboratory of Viral Oncology

Wenxuan Wang

Hainan Medical University - Department of Urology

Fei Wang

Southern Medical University - Shenzhen Key Laboratory of Viral Oncology

Jiaqi Fan

Southern Medical University - Shenzhen Key Laboratory of Viral Oncology

Jinan Guo

Jinan University of Second Clinical Medical Sciences - Department of Urology

Tao Wu

Southern Medical University - Department of Urology

Dongliang Lu

Southern Medical University - Department of Urology

Qingchun Zhou

Southern Medical University - Department of Urology

Zhuohao Liu

Southern Medical University - Shenzhen Key Laboratory of Viral Oncology

Yuliang Wang

Southern Medical University - Shenzhen Key Laboratory of Viral Oncology

Zhiqun Shang

Tianjin Medical University - Tianjin Institute of Urology

Franky Leung Chan

The Chinese University of Hong Kong (CUHK) - School of Biomedical Sciences

Wei Yang

Southern Medical University - Department of Pathology

Xin Li

Southern Medical University - Shenzhen Key Laboratory of Viral Oncology

Shanchao Zhao

Southern Medical University - Department of Urology

Qingyou Zheng

Southern Medical University - Department of Urology

Fei Wang

Hainan Medical University - Department of Urology

Dinglan Wu

Southern Medical University - Shenzhen Key Laboratory of Viral Oncology

More...

Abstract

Background: Current diagnosis tools for prostate cancer (PCa) such as serum PSA detection and prostate biopsy cannot distinguish dormant tumors from invasive malignancies, either be used as a prognosis marker for castration resistant prostate cancer (CRPC), the lethal stage of PCa patients. Exosomes have been widely investigated as promising biomarkers for various diseases. We aim to characterize the proteomic and metabolomic profile of exosomes and to evaluate their potential value for the diagnosis of PCa, especially CRPC. The functional role of some specific exosome biomarkers in the progression of CRPC was also investigated.

Methods: Integrated proteomics and metabolomics analysis were performed for plasma-derived exosomes collected from tumor-free controls (TFC), PCa and CRPC patients. Expression of specific exosomal proteins was further validated by targeting 4D-parallel reaction monitoring (PRM) mass spectrometry among the three cohorts. Tissue distribution and functional role of exosomal protein LRG1 was studied in clinical PCa tissue samples and cell line models.

Findings: Three potential exosomal protein markers were identified. The apolipoprotein E level in PCa samples was 1.7-fold higher than that in TFC (receiver operating characteristic [ROC] value, 0.74). Similarly, the levels of exosome-derived leucine-rich alpha2-glycoprotein 1 (LRG1) and inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) in the CRPC group were 1.7 and 2.04 times, respectively, higher than those in the PCa group (ROC values, 0.84 and 0.85, respectively), indicating that LRG1 and ITIH3 could serve as predictive markers for CRPC. For metabolic evaluation of exosomes, a series of differently expressed metabolites were identified, and a combined metabolite panel showed ROC value of 0.94 for distinguishing PCa from TFC and 0.97 for distinguishing CRPC from PCa.  Immunohistochemistry of tissue microarray showed that LRG1 protein was significantly upregulated in advanced prostate cancer and functional assay revealed that ectopic expression of LRG1 can significantly enhance the malignant phenotype of prostate cancer cells. More importantly, PCa cell derived LRG1-overexpressed exosomes remarkably promoted angiogenesis.

Interpretation: Integration of proteomics and metabolomics data yielded proteomic and metabolic signatures of plasma exosomes that may facilitate discrimination of CRPC from PCa and TFC patients, suggesting the potential of exosomal proteins and metabolites as CRPC markers. The study also confirmed the important role of exosomal protein LRG1 in PCa malignant progression.

Funding Information: This study was funded by the National Natural Science Foundation of China (No. 81872283, 81900801), Guangdong Basic and Applied Basic Research Foundation (No. 2019A1515011211), National Key R&D Program of China (MOST, No. 2018YFA0800404), China Postdoctoral Science Foundation funded project (No.2020T130279 and 3 2020M682812), Science and Technology Project of Shenzhen (No. JCYJ20180508163203807), Shenzhen Key Laboratory of Viral Oncology (No. ZDSYS201707311140430) and Sanming Project of Medicine in Shenzhen (No. SZSM201612023), Provincial Postgraduate Innovation Project of Hainan Province in 2020 (No.HYS2020- 379), Hainan Province Science and Technology Special Fund (grant no. ZDYF2021SHFZ096), Hainan Province Clinical Medical Center.

Declaration of Interests: The authors declare that no conflict of interest exists

Ethics Approval Statement: The study was approved by the human ethics committees of these hospitals. Written informed consent and clinical information were obtained from all patients.

Keywords: PCa, CRPC, Exosomes, proteomics, Metabolomics, Biomarkers, LRG1

Suggested Citation

Liu, Pengyu and Wang, Wenxuan and Wang, Fei and Fan, Jiaqi and Guo, Jinan and Wu, Tao and Lu, Dongliang and Zhou, Qingchun and Liu, Zhuohao and Wang, Yuliang and Shang, Zhiqun and Chan, Franky Leung and Yang, Wei and Li, Xin and Zhao, Shanchao and Zheng, Qingyou and Wang, Fei and Wu, Dinglan, Alterations of Plasma Exosomal Proteins and Metabolites are Associated with the Progression of Castration-Resistant Prostate Cancer. Available at SSRN: https://ssrn.com/abstract=4064645 or http://dx.doi.org/10.2139/ssrn.4064645

Pengyu Liu

Southern Medical University - Shenzhen Key Laboratory of Viral Oncology ( email )

Shenzhen
China

Wenxuan Wang

Hainan Medical University - Department of Urology ( email )

Haikou, Hainan Province
China

Fei Wang

Southern Medical University - Shenzhen Key Laboratory of Viral Oncology ( email )

Shenzhen
China

Jiaqi Fan

Southern Medical University - Shenzhen Key Laboratory of Viral Oncology ( email )

Shenzhen
China

Jinan Guo

Jinan University of Second Clinical Medical Sciences - Department of Urology ( email )

Shenzhen, Guangdong
China

Tao Wu

Southern Medical University - Department of Urology ( email )

China

Dongliang Lu

Southern Medical University - Department of Urology ( email )

China

Qingchun Zhou

Southern Medical University - Department of Urology ( email )

China

Zhuohao Liu

Southern Medical University - Shenzhen Key Laboratory of Viral Oncology ( email )

Shenzhen
China

Yuliang Wang

Southern Medical University - Shenzhen Key Laboratory of Viral Oncology ( email )

Shenzhen
China

Zhiqun Shang

Tianjin Medical University - Tianjin Institute of Urology ( email )

Tianjin
China

Franky Leung Chan

The Chinese University of Hong Kong (CUHK) - School of Biomedical Sciences ( email )

China

Wei Yang

Southern Medical University - Department of Pathology ( email )

Guangzhou
China

Xin Li

Southern Medical University - Shenzhen Key Laboratory of Viral Oncology ( email )

Shenzhen
China

Shanchao Zhao

Southern Medical University - Department of Urology ( email )

China

Qingyou Zheng

Southern Medical University - Department of Urology ( email )

China

Fei Wang

Hainan Medical University - Department of Urology ( email )

Haikou, Hainan Province
China

Dinglan Wu (Contact Author)

Southern Medical University - Shenzhen Key Laboratory of Viral Oncology ( email )

Shenzhen
China

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