Abstract
Hereditary tyrosinemia type 1 (HT1) is a severe inborn error of metabolism, impacting the tyrosine catabolic pathway with a high incidence of hepatocellular carcinoma (HCC). Using a HT1 murine model, we investigated the changes in profiles of circulating and hepatic miRNAs. The aim was to determine if plasma miRNAs could be used as non-invasive markers of liver damage in HT1 progression. Plasma and liver miRNAome was determined by deep sequencing after HT1 phenotype was induced. Sequencing analysis revealed deregulation of several miRNAs including let-7/miR-98 family, miR-21 and miR-148a, during manifestation of liver pathology. Three miRNAs (miR-98, miR-200b, miR-409) presenting the highest plasmatic variations among miRNAs found in both plasma and liver and with >1000 reads in at least one plasma sample, were further validated by RT-qPCR. Two of these miRNAs have protein targets involved in HT1 and significant changes in their circulating levels are detectable prior an increase in protein expression of alpha-fetoprotein, the current biomarker for HCC diagnosis. Future assessment of these miRNAs in HT1 patients and their association with liver neoplastic lesions might designate these molecules as potential biomarkers for monitoring HT1 damage progression, improving diagnosis for early HCC detection and the design of novel therapeutic targets.
Highlights
Hereditary tyrosinemia type 1 (HT1, OMIM 276700) is a rare inherited metabolic disease associated with a high risk of liver cancer development and usually fatal before two years of age if not treated effectively
We focused on miRNAs present in both plasma and liver to detect plasmatic variations likely related to the HT1 liver pathology (721 mouse miRNAs)
Gene ontology terms classification of the potential miRNAs targets[21], revealed enrichment in important biological processes like metabolic regulation, apoptosis, immune system process, cell-to-cell communication, protein transport and localization (Fig. 2b). Together these results suggest a general breakdown of tissue integrity and an increase in immune responses and tissue repairing processes after NTBC interruption in fah−/− mice suffering of progressive liver failure
Summary
Hereditary tyrosinemia type 1 (HT1, OMIM 276700) is a rare inherited metabolic disease associated with a high risk of liver cancer development and usually fatal before two years of age if not treated effectively (reviewed in[1]). The combination of NTBC (2-(2-nitro-trifluoromethylbenzoyl)-1,3-cyclohexanedione) intake with a low-tyrosine diet, and liver transplantation for the most severe cases, represent the only treatments available for this disease[4]. This regimen prevents liver and kidney dysfunction in patients[5], affected individuals can still develop several chronic complications including cirrhosis with a high risk of HCC6,7. Patients monitoring is not completely effective since almost 80% of small HCCs foci do not show increase in AFP levels and liver image sensitivity is not effective in detecting small liver lesions[8,9]. We examined the genome-wide expression profile of miRNAs in the fah−/− mouse[17] after induction of the HT1 phenotype, in order to evaluate the potential of using circulating miRNAs as a non-invasive method to assess HT1 liver damage progression
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