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Phosphoproteomics Identifies Significant Biomarkers Associated with the Proliferation and Metastasis of Prostate Cancer.

ABSTRACT: The spider peptide toxins HNTX-III and JZTX-I are a specific inhibitor and activator of TTX-S VGSCs, respectively. They play important roles in regulating MAT-LyLu cell metastasis in prostate cancer. In order to identify key biomarkers involved in the regulation of MAT-LyLu cell metastasis, iTRAQ-based quantitative phosphoproteomics analysis was performed on cells treated with HNTX-III, JZTX-I and blank. A total of 554 unique phosphorylated proteins and 1779 distinct phosphorylated proteins were identified, while 55 and 36 phosphorylated proteins were identified as differentially expressed proteins in HNTX-III and JZTX-I treated groups compared with control groups. Multiple bioinformatics analysis based on quantitative phosphoproteomics data suggested that the differentially expressed phosphorylated proteins and peptides were significantly associated with the migration and invasion of prostate tumors. Specifically, the toxins HNTX-III and JZTX-I have opposite effects on tumor formation and metastasis by regulating the expression and phosphorylation level of causal proteins. Herein, we highlighted three key proteins EEF2, U2AF2 and FLNC which were down-regulated in HNTX-III treated cells and up-regulated in JZTX-I treated cells. They played significant roles in cancer related physiological and pathological processes. The differentially expressed phosphorylated proteins identified in this study may serve as potential biomarkers for precision medicine for prostate cancer in the near future.

SUBMITTER: Xu R

PROVIDER: S-EPMC8402417 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Prostate Cancer (PCa) overdiagnosis and overtreatment, as a consequence of the limited specificity of current detection and prognostication methods, remains a major challenge in clinical practice. Therefore, development and validation of new molecular biomarkers amenable of detecting clinically significant disease is crucial. MicroRNAs (miRNA) deregulation is common in cancer, constituting potential non-invasive biomarkers for PCa detection and prognostication. Herein, we evaluated the screening and prognostic biomarker potential of two onco-microRNAs (miR-182-5p and miR-375-3p) in liquid biopsies (plasma) of PCa patients with clinically localized disease undergoing curative-intent treatment. A first cohort of 98 PCa and 15 normal prostates were used to assess PCa-specificity of miR-182-5p in tissues. A cohort composed of PCa 252 patients and 52 asymptomatic controls allowed for assessment of diagnostic and prognostic value in plasmas. After RNA extraction from tissue and plasma samples, cDNA synthesis specific for miRNAs was performed followed by measurement of miR-182-5p and miR-375-3p relative expression by RT-qPCR, using U6 snRNA gene as reference. MiR-182-5p was significantly overexpressed in PCa tissues (p < 0.0001) and in plasma of PCa patients (p = 0.0020), compared to respective controls. Moreover, miR-182-5p expression identified PCa with AUC = 0.81 (95% CI: 0.725-0.892, p = 0.0001) in tissue and with 77% specificity and 99% NPV (AUC = 0.64, 95% CI: 0.561-0.709, p = 0.0021) in plasma. Both circulating miR-182-5p and miR-375-3p levels associated with more advanced pathologic stage and the former was significantly higher in patients that developed metastasis (p = 0.0145). Indeed, at the time of diagnosis, circulating miR-375-3p levels predicted which patients would develop metastasis, with almost 50% sensitivity, 76% specificity, and a NPV of 89% (AUC = 0.62, 95% CI: 0.529-0.713, p = 0.0149). We conclude that these two circulating miRNAs might be clinical useful as non-invasive biomarkers for detection and prediction of metastasis development at the diagnosis together with clinical variables used in routine practice.

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Phosphoproteomics Identifies Significant Biomarkers Associated with the Proliferation and Metastasis of Prostate Cancer.

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