Circulating microRNAs, miR-939, miR-595, miR-519d and miR-494, Identify Cirrhotic Patients with HCC

Abstract

The performance of circulating biomarkers for the diagnosis of hepatocellular carcinoma (HCC) is sub-optimal. In this study we tested circulating microRNAs as biomarkers for HCC in cirrhotic patients by performing a two stage study: a discovery phase conducted by microarray and a validation phase performed by qRT-PCR in an independent series of 118 patients. Beside miRNAs emerged from the discovery phase, miR-21, miR-221, miR-519d were also tested in the validation setting on the basis of literary and tissue findings. Deregulated microRNAs were assayed in HCC-derived cells in the intracellular compartment, cell culture supernatant and exosomal fraction. Serum and tissue microRNA levels were compared in 14 patients surgically treated for HCC. From the discovery study, it emerged that seven circulating microRNAs were differentially expressed in cirrhotic patients with and without HCC. In the validation set, miR-939, miR-595 and miR-519d were shown to differentiate cirrhotic patients with and without HCC. MiR-939 and miR-595 are independent factors for HCC. ROC curves of miR-939, miR-595 and miR-519d displayed that AUC was higher than AFP. An exosomal secretion of miR-519d, miR-21, miR-221 and miR-1228 and a correlation between circulating and tissue levels of miR-519d, miR-494 and miR-21 were found in HCC patients. Therefore, we show that circulating microRNAs deserve attention as non-invasive biomarkers in the diagnostic setting of HCC and that exosomal secretion contributes to discharging a subset of microRNAs into the extracellular compartment.

Exosome-based liquid biopsy in the management of hepatocellular carcinoma

“…A whole microRNAome microarray analysis was applied to explore dysregulated expression of miRNAs in patients with cirrhosis, early, intermediate and advanced HCC. This study identified exosome-mediated dysregulation of circulatory miRNAs, miR-519d, miR-21, miR-221 and miR-1228 [17] . A significant reduction in miR-320a level was detected by miRNA sequencing of exosomes derived from cancer-associated stromal fibroblasts (CAFs) when compared to corresponding paracancer fibroblasts (PAFs) of 6 HCC patients [44] .…”

“…Circulating miRNAs, miR-939, miR-595, miR-519d and miR-494 could identify cirrhotic patients with HCC. Upon comparison of serum and tissue miR levels in 14 patients surgically treated for HCC, a correlation between circulating and tissue levels of miR-519d, miR-494 and miR-21 was found in HCC patients [17] . A whole microRNAome microarray analysis was applied to explore dysregulated expression of miRNAs in patients with cirrhosis, early, intermediate and advanced HCC.…”

“…The role of exosomes in the areas of diagnosis, prognosis and treatment of tumours have been intensively investigated in many cancers, including HCC [13,16] . Tumour cell-derived exosomes were shown to carry and transfer oncogenes, pathogens and microRNAs [17] . Understanding the role of exosomes and their relevance to HCC offers the potential for new biomarkers for diagnosis and new druggable targets for treatment.…”

Enlarged selection criteria for hepatocellular cancer: is the upper limit needed?

“…The potential advantage over physical biopsies is dual, as the analysis is not limited to a single nodule, while the risk of dissemination is completely avoided. Exosomes specific to HCC have already been identified (25,26) and challenged on their efficacy in predicting recurrence after LT (27). The results are encouraging and the future of this technology is certainly bright.…”

Tissue microRNAs as Cancer Tissue Biomarkers

“…Distinguishing HCC are high circulating levels of miR-520b. In an in vivo study, high levels of miR-595 and miR-765 in plasma resulted in accurate diagnoses [15]. Also, a wide screen of miRNAs in blood plasma was done to measure accuracy of diagnoses for colorectal cancer.…”