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Published on: August 19, 2025
Quantitative proteomic analysis in HCV-induced HCC reveals sets of proteins with potential significance for racial
Insights
Hepatocellular carcinoma (HCC) is more common in African Americans due to unknown reasons. This study found distinct protein expression in HCC tissues, suggesting differential regulation of hepatocyte nuclear factor 4 alpha may explain racial disparities.
Area of Science:
- Hepatocellular carcinoma (HCC) research
- Proteomics and molecular biology
- Racial health disparities
Background:
- Hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) incidence and mortality are disproportionately higher in African Americans (AA) compared to Caucasian Americans (CA) in the U.S.
- The underlying biological mechanisms contributing to this racial disparity in HCC rates remain largely unknown.
- There is a critical need to identify novel molecular signatures for HCV disease progression to address this health disparity.
Purpose of the Study:
- To identify differentially expressed proteins in cirrhotic and HCC tissues compared to normal tissues.
- To investigate potential molecular mechanisms underlying racial disparities in HCV-induced HCC.
- To discover novel molecular signatures for HCC progression.
Main Methods:
- Differential proteomics using isobaric labeling tags for relative and absolute quantitation (iTRAQ) and MS/MS analysis.
- Analysis of protein expression in cirrhotic (CIR) and HCC tissues from Caucasian American (CA) patients compared to normal tissues.
- Validation of candidate protein expression in independent cohorts of CA and African American (AA) tissues using qRT-PCR or Western blotting.
Main Results:
- A total of 238 unique proteins were identified, with approximately 15% showing differential expression between normal, CIR, and HCC groups.
- Racially distinct alterations in protein expression were observed, with Transferrin (TF) and Apolipoprotein A1 (APOA1) showing significantly higher expression in AA HCC tissues.
- Hepatocyte nuclear factor 4 alpha (HNF4a) protein was downregulated in AA, suggesting differential dysregulation of HNF4a transcriptional activity may contribute to racial disparities in HCC.
Conclusions:
- This study utilized iTRAQ-based tissue proteomics to identify novel molecular signatures in HCV-induced HCC.
- The identified proteins provide potential molecular explanations for the biochemical mechanisms contributing to HCC racial disparities.
- Further research into these molecular signatures can improve clinical outcomes for affected populations.
Background:
The 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.
Methods:
We 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.
Results:
A total of 238 unique proteins were identified. Of those, around 15% were differentially expressed between normal, CIR & 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 factor4a (HNF4a) 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 HNF4a transcriptional activity.
Conclusion:
This 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 mechanism(s) that may play a role in HCC racial disparities.
