Prognostic MicroRNA Panel for HCV-Associated HCC: Integrating Computational Biology and Clinical Validation

Abstract

Early detection of hepatocellular carcinoma (HCC) will reduce morbidity and mortality rates of this widely spread disease. Dysregulation in microRNA (miRNA) expression is associated with HCC progression. The objective is to identify a panel of differentially expressed miRNAs (DE-miRNAs) to enhance HCC early prediction in hepatitis C virus (HCV) infected patients. Candidate miRNAs were selected using a bioinformatic analysis of microarray and RNA-sequencing datasets, resulting in nine DE-miRNAs (miR-142, miR-150, miR-183, miR-199a, miR-215, miR-217, miR-224, miR-424, and miR-3607). Their expressions were validated in the serum of 44 healthy individuals, 62 non-cirrhotic HCV patients, 67 cirrhotic-HCV, and 72 HCV-associated-HCC patients using real-time PCR (qPCR). There was a significant increase in serum concentrations of the nine-candidate miRNAs in HCC and HCV patients relative to healthy individuals. MiR-424, miR-199a, miR-142, and miR-224 expressions were significantly altered in HCC compared to non-cirrhotic patients. A panel of five miRNAs improved sensitivity and specificity of HCC detection to 100% and 95.12% relative to healthy controls. Distinguishing HCC from HCV-treated patients was achieved by 70.8% sensitivity and 61.9% specificity using the combined panel, compared to alpha-fetoprotein (51.4% sensitivity and 60.67% specificity). These preliminary data show that the novel miRNAs panel (miR-150, miR-199a, miR-224, miR-424, and miR-3607) could serve as a potential non-invasive biomarker for HCC early prediction in chronic HCV patients. Further prospective studies on a larger cohort of patients should be conducted to assess the potential prognostic ability of the miRNAs panel.

Clinical Application of Different Liquid Biopsy Components in Hepatocellular Carcinoma

“…Nine miRNAs (miR-142, miR-150, miR-183, miR-199a, miR-215, miR-217, miR-224, miR-424 and miR-3607) were discovered to be differentially expressed in HCC and HCV patients compared to healthy volunteer serum specimens. The investigators combined miR-150, miR-199a, miR-224, miR-424 and miR-3607 together as an early detection instrument and it did show better sensitivity and specificity [135]. miR-497 and miR-1246 levels not only related to TNM stages and metastasis in HCC but also to some extent, could act as a prognostic predictor [118].…”

MicroRNAs as Plasma Biomarkers of Hepatocellular Carcinoma in Patients with Liver Cirrhosis—A Cross-Sectional Study

“…Furthermore, many miRNAs may be both up-and down-regulated in HCC patients, which could lead to analytical difficulties in clinical practice. However, a small number are reported to be upregulated in HCC patients in more than a few publications, the most common of which are miR-21 [11,15,23,[26][27][28], miR-29 [22,26,[29][30][31], miR-192 [11,15,30], miR-199 [15,31,32], miR-221 [26,33,34], miR-222 [26,34], and miR-224 [18,32,35]. Of four meta-analyses that evaluated the diagnostic value of miRNAs for HCC detection, three cautiously encouraged their role as biomarkers [27,36,37], whereas one concluded that adding miRNA to the protein biomarkers AFP or DCP did not improve the diagnostic performance [28].…”

Патогенез Канцерогенного Действия Вируса Герпеса Человека 8 Типа, Вируса Гепатита B И Вируса Гепатита С

“…О связи ВГВ с возникновением ГЦК свидетельствует и то, что у подавляющего большинства больных ГЦК (в отличие от пациентов без рака) выявляются интеграции ДНК HBV в геном гепатоцитов. Причем относительная распространенность вирусных интеграций в тканях опухоли намного выше, чем в окружающих тканях печени [7].…”

“…При сравнении микроРНК в ВГB-и ВГC-ассоциированных ГЦК было выяснено, что при ГЦК, ассоциированной с ВГС, дифференциально дерегулируемые микроРНК связаны с регуляцией иммунного ответа, презентацией антигена, клеточным циклом или липидным метаболизмом, в то время как при ГЦК, ассоциированной с ВГВ, они скорее вовлечены в пути, регулирующие гибель клеток, повреждение ДНК или передачу сигнала [7].…”