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Journal of Translational Medicine

, 11:239

Disease Biomarkers

Abstract

BackgroundThe incidence and mortality of hepatitis C virus HCV-induced hepatocellular carcinoma HCC is higher in African Americans AA than other racial-ethnic groups in the U.S., but the reasons for this disparity are unknown. There is an urgent need for the discovery of novel molecular signatures for HCV disease progression to understand the underlying biological basis for this cancer rate disparity to improve the clinical outcome.

MethodsWe performed differential proteomics with isobaric labeling tags for relative and absolute quantitation iTRAQ and MS-MS analysis to identify proteins differentially expressed in cirrhotic CIR and HCC as compared to normal tissues of Caucasian American CA patients. The raw data were analyzed using the ProteinPilot v3.0. Searches were performed against all known sequences populating the Swiss-Prot, Refseq, and TrEMBL databases. Quality control analyses were accomplished using pairwise correlation plots, boxplots, principal component analysis, and unsupervised hierarchical clustering. Supervised analysis was carried out to identify differentially expressed proteins. Candidates were validated in independent cohorts of CA and AA tissues by qRT-PCR or Western blotting.

ResultsA total of 238 unique proteins were identified. Of those, around 15% were differentially expressed between normal, CIR and HCC groups. Target validation demonstrates racially distinct alteration in the expression of certain proteins. For example, the mRNA expression levels of transferrin TF were 2 and18-fold higher in CIR and HCC in AA as compared to CA. Similarly; the expression of Apolipoprotein A1 APOA1 was 7-fold higher in HCC of AA. This increase was mirrored in the protein expression levels. Interestingly, the level of hepatocyte nuclear factor4α HNF4α protein was down regulated in AA, whereas repression of transcription is seen more in CA compared to AA. These data suggest that racial disparities in HCC could be a consequence of differential dysregulation of HNF4α transcriptional activity.

ConclusionThis study identifies novel molecular signatures in HCV-induced HCC using iTRAQ-based tissue proteomics. The proteins identified will further enhance a molecular explanation to the biochemical mechanisms that may play a role in HCC racial disparities.

KeywordsHepatocellular carcinoma Hepatitis C Tissue proteomics Isobaric tags for relative and absolute quantification iTRAQ Cancer racial disparity AbbreviationsHCVHepatitis C virus

HCCHepatocellular carcinoma

iTRAQIsobaric labeling tags for relative and absolute quantitation

CIRCirrhosis

CACaucasian Americans

AAAfrican Americans

TFTransferrin

APOA1Apolipoprotein A1

HNF4αHepatocyte nuclear factor4α

FLNAFilamin A

qRT-PCRQuantitative real-time RT-PCR

WBWestern blotting

PCAPrincipal component analysis

IPAIngenuity pathway analysis

DEPDifferentially expressed proteins

NRNuclear receptor.

Electronic supplementary materialThe online version of this article doi:10.1186-1479-5876-11-239 contains supplementary material, which is available to authorized users.

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Autor: Simon T Dillon - Manoj K Bhasin - Xiaoxing Feng - David W Koh - Sayed S Daoud

Fuente: https://link.springer.com/







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