INTRODUCTION: The presence of vascular invasion is known to be a strong predictor of hepatocellular carcinoma (HCC) recurrence after resection or transplant, but no clinically useful molecular markers for this phenomenon are available yet.

METHODS: We performed miRNA expression profiling on 124 HCC tumor nodules from 77 patients using oligonucleotide microarrays containing 850 human miRNAs. 47% of the 77 patients had vascular invasion on explant analysis, conferring a 6.2 greater odds for recurrence (p<0.001). All tumor nodules from patients with multifocal disease were individually analyzed and histopathologic review was performed on each nodule to confirm macro- or microvascular invasion, thereby maximizing the sensitivity of our analysis. Normalized data were analyzed using Partek Genomic Suite v6.6. Verification of the miR-125b and miR-194 expression profiles were confirmed with qRT-PCR.

RESULTS: A total of 43 miRNAs were differentially expressed (p<0.01, 18 upregulated and 25 downregulated), including miR-18a, -99a, -125b, -194, -365, -501, -877, -1180, -1243, and -1273. These 10 miRNAs are components of a biomarker previously shown to be predictive of HCC recurrence after transplant. TGF beta, which has been shown experimentally to control HCC vascular invasion, is a known target of both miR-99a and miR-365. Furthermore, experimental evidence exists for the roles of miR-125b in tumor invasion and miR-194 in angiogenesis. In comparing patients with macro- versus microvascular invasion, 148 miRNAs are differentially expressed (p<0.05, 76 upregulated and 72 downregulated), suggesting that these two entities are readily distinguishable using miRNA expression profiles.

CONCLUSIONS: Further development of robust miRNA biomarkers for vascular invasion will enhance our abilities to prognosticate, select, and treat patients with HCC. Knowledge of such miRNAs and their downstream mRNA and protein targets will deepen our understanding of HCC biology in general.

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