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Identification of miR-151a as a universal endogenous control for exosome cargo normalization in human cancer

ABSTRACT: The exosomal particles in the blood of cancer patients possess many times more tumor markers than free circulating. Among these elements, miRNAs have great biomedical relevance due to their stability and feasible detection. However, there is not available in the market any reliable endogenous control for the exosomal compartment, nor specific for the miRNA content, preventing the obtainment of standardization measures in cancer liquid-biopsy. In this study, we firstly identified three miRNAs out of a panel of nine potential normalizers that arised from an integrative analysis comparing the global miRNA exosomal profile by miRNA-seq of six lung and ovarian human cancer cell lines under different chemotherapy conditions. Their value as normalizers were also tested in 14 additional human cancer cell lines from different tumor types and after radiotherapy and an alternative chemotherapy treatment. Its translational validation comprised 124 prospective samples, 70 plasma from NSCLC patients, 12 from glioblastoma patients, 10 healthy donors and 16 paired samples from plasma and ascites fluid from ovarian cancer patients. The variability and normalizing properties were tested in comparison with the tissue-origin gold standard miR-16. Our results indicate that miR-151a is constantly represented in the exosomal content with minimal variability compared with miR16 independently of many conditions tested, providing for the first time a universal normalizer for the exosomal compartment that will impact the use of liquid biopsy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE204944 | GEO | 2023/05/26

REPOSITORIES: GEO

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Project description:Background/Aim: We investigated alterations in the expression of serum exosomal miRNAs with the progression of liver fibrosis and evaluated their clinical applicability as biomarkers. Methods: This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. Methods: This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. Results: NGS data revealed that exosomal miR-660-5p, miR-125a-5p, and miR-122 expression were changed significantly with the progression of liver fibrosis, of which miR-122 exhibited high read counts enough to be used as a biomarker. The level of exosomal miR-122 decreased as the pathologic fibrosis grade progressed and patients with biopsy-proven advanced fibrosis had significantly lower levels of exosomal miR-122 (P < 0.001) than those without advanced fibrosis. Exosomal miR-122 exhibited a fair performance in discriminating advanced fibrosis especially in combination with fibrosis-4 score and transient elastography. In a subgroup of patients with a non-viral etiology of liver disease, the performance of exosomal miR-122 as a biomarker was greatly improved. Inhibition of miR-122 expression increased the proliferation of the human hepatic stellate cell line, LX-2, and upregulated the expression of various fibrosis related proteins. Conclusion: Exosomal miR-122 may serve as a useful non-invasive biomarker for liver fibrosis, especially in patients with non-viral etiologies of chronic liver disease.

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Identification of miR-151a as a universal endogenous control for exosome cargo normalization in human cancer

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