Abstract
Simple SummaryExosomes, carrying small non-coding RNA (miRNA), are known to play a pivotal role in the process of tumor progression. In this prospective study, we identified miR-16, miR-146a, miR-192, and miR- 221 to be significantly deregulated in the plasma of patients with hepatocellular carcinoma (HCC) compared to patients with liver cirrhosis and healthy individuals. MiR-146a revealed diagnostic potential to differentiate HCC patients from liver cirrhosis patients with a sensitivity of 81% and a specificity of 58% in logistic regression model. Furthermore, miR- 192 independently correlated with overall survival in patients with HCC.We aimed to identify a specific microRNA (miRNA) pattern to determine diagnostic and prognostic value in plasma exosomes of hepatocellular carcinoma (HCC) patients. A two-stage study was carried out: exosomal miRNAs were quantified in plasma of HCC patients and healthy individuals by PCR-based microarray cards containing 45 different miRNAs (training cohort). Then, four deregulated miRNAs (miR-16, miR-146a, miR-192, and miR-221) were quantified in the validation analysis using exosomes derived from 85 HCC patients, 50 liver cirrhosis patients, and 20 healthy individuals. Exosomal miR-146a (p = 0.0001), miR-192 (p = 0.002) and miR-221 (p = 0.032) were upregulated only in HCC patients. Repeated 10-fold cross validation showed that miR-146a differentiated HCC from liver cirrhosis patients with AUC of 0.80 ± 0.14 (sensitivity: 81 ± 13%, specificity: 58 ± 22%) in a logistic regression model. High miR-192 presence is associated with poor overall survival (OS) in all HCC patients (p = 0.027) and was predictor of OS in HCC patients in an uni- and multivariate Cox regression model. Moreover, decreased miR-16 levels correlated with OS in liver cirrhosis patients (p = 0.034). Our results emphasized that exosomes secreted into the plasma carry differentially expressed miRNAs of which in particular, miR-192, miR-146, and miR-16 are promising diagnostic and prognostic markers for both HCC and liver cirrhosis patients.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary liver tumor and one of the leading cause of cancer related death worldwide [1]
Extraction of exosomes from three plasma samples was verified by Western Blot using an antibody specific for the exosomal marker CD63
Suheiro et al recently demonstrated that alterations in the expression of exosomal miR-122 is associated with survival in HCC patients treated with TACE, underlining the ability of miRNAs to serve as biomarkers for therapy monitoring [30]
Summary
Hepatocellular carcinoma (HCC) is the most common primary liver tumor and one of the leading cause of cancer related death worldwide [1]. Liver function is incorporated into the most relevant clinical classification systems (e.g., Okuda system, Barcelona Clinic Liver Cancer Classification (BCLC) and Cancer of Liver Italian Program (CLIP) classification). This illustrates the complexity of tumor therapy and the poor prognosis in patients with HCC and liver cirrhosis [5,6,7,8]. As therapeutic options for patients with advanced HCC have improved gradually over the past few years, it is crucial to identify prognostic markers predicting tumor progression and deterioration of the liver function in order to switch patients to more effective treatment lines [9,10,11,12]
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