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Here, in silico, ex vivo and in vitro data were combined to identify liver\u2010specific exosomal miRNAs as an early diagnostic marker for HCC. Transcriptome profiling for mRNA and small RNA in same HCV\u2010HCC and normal liver tissues followed by cross\u2010validation of 41 deregulated miRNAs (log<jats:sub>2<\/jats:sub>FoldChange\u2009&gt;\u20091.5, <jats:italic>P<\/jats:italic><jats:sub>adj<\/jats:sub>\u2009&lt;\u2009.1) with GEO\/TCGA datasets of HCV\/HBV related HCC vs normal\/adjacent tissue revealed three miRNAs were commonly deregulated (miR\u201010b\/miR\u201021\/miR\u2010182) among all HCC irrespective of viral etiology. Targets of top deregulated miRNAs were identified by TargetScan\/miRwalk and validated in mRNA transcriptome data followed by Panther\/Gene Ontology enrichment\/Cytoscape analysis suggested that targets were mostly from carcinogenesis pathways. Hence, those miRNAs were validated in normal and HCV\u2010HCC tissues by qRT\u2010PCR and subsequently in plasma\u2010derived\u2010exosomes of both HBV\/HCV infected non\u2010HCC (chronic hepatitis [CH]\/liver cirrhosis [LC]) and HCC samples, and in liver\u2010specific Anti\u2010Asgr2 immuno\u2010enriched exosomes. Exosomes were verified using Nanosight\/TEM\/immune\u2010blotting with anti\u2010Alix\/anti\u2010GRP78\/anti\u2010Asgr2. Along with miR\u201021\u20105p, miR\u201010b\u20105p\/miR\u2010221\u20103p\/miR\u2010223\u20103p was found significantly upregulated in the exosome of HCC patients than CH\/non\u2010HCC. The comparable expression pattern was seen in anti\u2010Asgr2 immuno\u2010precipitated exosomes. Interestingly, the AFP level was found below 250\u2009ng\/mL in about 94% of HCV\u2010HCC and 62% of HBV\u2010HCC patients. ROC analysis showed that miR\u201010b\u20105p\u2009+\u2009miR\u2010221\u20103p\u2009+\u2009miR\u2010223\u20103p\u2009+\u2009miR\u201021\u20105p could differentiate CH\/non\u2010HCC(CH\u2009+\u2009LC) from HCC with AUROC: 0.86 (97.5% CI: 0.77\u20100.94)\/0.80 (97.5% CI: 0.70\u20100.89), sensitivity: 74%\/58% and specificity: 86%\/95% while miR\u201010b\u20105p\u2009+\u2009miR\u2010221\u20103p\u2009+\u2009miR\u2010223\u20103p showed AUROC: 0.84 (97.5% CI: 0.74\u20100.94)\/0.74 (97.5% CI: 0.63\u20100.84), sensitivity: 86%\/86% and specificity:66%\/53% for low AFP\u2010HCC vs CH\/non\u2010HCC, respectively, having better sensitivity than the combination of four miRNAs. Multivariate analysis further revealed low Albumin and high miR\u201021\u20105p as probable independent risk factor for HCC.<\/jats:p>","DOI":"10.1002\/ijc.33111","type":"journal-article","created":{"date-parts":[[2020,5,22]],"date-time":"2020-05-22T10:05:19Z","timestamp":1590141919000},"page":"2934-2947","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":118,"title":["The exosome encapsulated <scp>microRNAs<\/scp> as circulating diagnostic marker for hepatocellular carcinoma with low alpha\u2010fetoprotein"],"prefix":"10.1002","volume":"147","author":[{"given":"Suchandrima","family":"Ghosh","sequence":"first","affiliation":[{"name":"Centre for Liver Research, School of Digestive and Liver Diseases Institute of Post Graduate Medical Education and Research  Kolkata West Bengal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayantani","family":"Bhowmik","sequence":"additional","affiliation":[{"name":"Centre 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