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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 2022More...
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
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