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Clinical Impact of Exosomal microRNA in Liver Fibrosis: Based on Next-Generation Sequencing Analysis
( Young Chang ),( Jae-a Han ),( Suk Min Kang ),( Soung Won Jeong ),( Tom Ryu ),( Han Seul Park ),( Jeong-ju Yoo ),( Sae Hwan Lee ),( Sang Gyune Kim ),( Young Seok Kim ),( Hong Soo Kim ),( So Young Jin 대한간학회 2021 춘·추계 학술대회 (KASL) Vol.2021 No.1
Clinical Impact of Exosomal microRNA as a Novel Biomarker of Liver Fibrosis
( Young Chang ),( Jae-a Han ),( Suk Min Kang ),( Soung Won Jeong ),( Tom Ryu ),( Han Seul Park ),( Jeong-ju Yoo ),( Sae Hwan Lee ),( Sang Gyune Kim ),( Young Seok Kim ),( Hong Soo Kim ),( So Young Jin 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1
Aims: Many approaches have been suggested for the non-invasive diagnosis of liver fibrosis, including the use of serum biomarkers and ultrasound-based elastography, but none has yet replaced liver biopsy. MicroRNAs (miRNAs) have been suggested as potential diagnostic tools for liver diseases. 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 a large-volume academic hospital in Korea. Exosomes were extracted from serum samples, and next-generation sequencing (NGS) of miRNAs was conducted in patients from different stages of liver fibrosis. Differential expression of miRNAs was quantified using targeted real-time quantitative polymerase chain reaction (RT-qPCR). A model was derived to discriminate advanced fibrosis based on miRNA levels using multivariate logistic regression. The performance of this model was evaluated and compared using area under the receiver operator characteristic (ROC) curve (AUC) and De- Long’s test. Results: NGS data revealed the relationship between exosomal miR-122 expression and liver fibrosis progression. The level of miR-122 decreased as the pathologic fibrosis grade progressed from stage 0 to 4. 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 with an AUC of 0.77, which improved to 0.86 in combination with fibrosis-4 score (FIB-4) and transient elastography (TE). This value was higher than that reported for any other non-invasive modalities, including TE (AUC of 0.80) or FIB-4 (AUC of 0.57) alone. In a subgroup of patients with a non-viral etiology of liver disease, the performance of exosomal miR-122 as a biomarker improved, evident from the increase in the AUC value to 0.87. In this subpopulation, the combination model of miR- 122, FIB-4, and TE showed the best discrimination ability (AUC of 0.90), which was significantly higher than that of TE alone (AUC of 0.83; DeLong’s test P=0.046). Inhibition of miR-122 expression increased the proliferation of the human hepatic stellate cell line, LX-2, and upregulated the expression of collagen- 1A, a-smooth muscle actin, fibronectin, and transforming growth factor-ß. Conclusions: Exosomal miR-122 may serve as a novel biomarker for discriminating advanced liver fibrosis, and its accuracy may enhanced in combination with other non-invasive tests such as FIB-4 and TE.