Alterations of plasma exosomal proteins and motabolies are associated with the progression of castration-resistant prostate cancer

Liu，Pengyu1,11; Wang，Wenxuan12; Wang，Fei1; Fan，Jiaqi1; Guo，Jinan3; Wu，Tao4; Lu，Dongliang4; Zhou，Qingchun4; Liu，Zhuohao1; Wang，Yuliang1; Shang，Zhiqun5; Chan，Franky Leung6; Yang，Wei7,8; Li，Xin1; Zhao，Shan Chao9,10; Zheng，Qingyou4; Wang，Fei2; Wu，Dinglan1

2023-12-01

10.1186/s12967-022-03860-3

Journal of Translational Medicine   Impact Factor & Quartile

1479-5876

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 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. We also investigate the functions of some specific exosome biomarkers in the progression of CRPC. 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 were further validated by targeted 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. Results: 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 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 metabolomic evaluation of exosomes, a series of differentially 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. Conclusion: Integration of proteomics and metabolomics data generated 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.

Biomarkers CRPC Exosomes Metabolomics PCa Proteomics

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English

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Natural Science Foundation of Guangdong Province[2021A1515011085];National Natural Science Foundation of China[81872283];National Natural Science Foundation of China[81900801];Science and Technology Planning Project of Shenzhen Municipality[JCYJ20180508163203807];Sanming Project of Medicine in Shenzhen[SZSM201612023];

Research & Experimental Medicine

Medicine, Research & Experimental

WOS:000927570800001

BMC

2-s2.0-85146743089

Scopus

1.Shenzhen Key Laboratory of Viral Oncology,The Clinical Innovation & Research Center (CIRC),Shenzhen Hospital,Southern Medical University,Shenzhen,Guangdong Province,China
2.Department of Urology,Hainan General Hospital,Hainan Affiliated Hospital of Hainan Medical University,Haikou,Hainan Province,China
3.Department of Urology,Shenzhen People’s Hospital (The Second Clinical Medical College,Jinan University,The First Affiliated Hospital,Southern University of Science and Technology),Shenzhen,Guangdong Province,China
4.Department of Urology,Shenzhen Hospital,Southern Medical University,Shenzhen,Guangdong Province,China
5.Department of Urology,Tianjin Institute of Urology,The Second Hospital of Tianjin Medical University,Tianjin,300211,China
6.School of Biomedical Sciences,The Chinese University of Hong Kong,SAR,Hong Kong
7.Department of Pathology,School of Basic Medical Sciences,Southern Medical University,Guangzhou,510515,China
8.Department of Endocrinology and Metabolism,Zhujiang Hospital,Southern Medical University,Guangzhou,510280,China
9.Department of Urology,The Third Affiliated Hospital of Southern Medical University,Guangzhou,510500,China
10.Department of Urology,Nanfang Hospital,Southern Medical University,Guangzhou,510515,China
11.Department of Medical Genetics and Developmental Biology,School of Medicine,Southeast University,Nanjing,China
12.Department of Urology,Guangdong Hospital of Traditional Chinese Medicine,Zhuhai,Guangdong Province,519015,China

Liu，Pengyu,Wang，Wenxuan,Wang，Fei,et al. Alterations of plasma exosomal proteins and motabolies are associated with the progression of castration-resistant prostate cancer[J]. Journal of Translational Medicine,2023,21(1).

Liu，Pengyu.,Wang，Wenxuan.,Wang，Fei.,Fan，Jiaqi.,Guo，Jinan.,...&Wu，Dinglan.(2023).Alterations of plasma exosomal proteins and motabolies are associated with the progression of castration-resistant prostate cancer.Journal of Translational Medicine,21(1).

Liu，Pengyu,et al."Alterations of plasma exosomal proteins and motabolies are associated with the progression of castration-resistant prostate cancer".Journal of Translational Medicine 21.1(2023).