Abstract
Hepatocellular carcinoma (HCC) is the world’s third most widespread cancer. Currently available circulating biomarkers for this silently progressing malignancy are not sufficiently specific and sensitive to meet all clinical needs. There is an imminent and pressing need for the identification of novel circulating biomarkers to increase disease-free survival rate. In order to facilitate the selection of the most promising circulating protein biomarkers, we attempted to define an objective method likely to have a significant impact on the analysis of vast data generated from cutting-edge technologies. Current study exploits data available in seven publicly accessible gene and protein databases, unveiling 731 liver-specific proteins through initial enrichment analysis. Verification of expression profiles followed by integration of proteomic datasets, enriched for the cancer secretome, filtered out 20 proteins including 6 previously characterized circulating HCC biomarkers. Finally, interactome analysis of these proteins with midkine (MDK), dickkopf-1 (DKK-1), current standard HCC biomarker alpha-fetoprotein (AFP), its interacting partners in conjunction with HCC-specific circulating and liver deregulated miRNAs target filtration highlighted seven novel statistically significant putative biomarkers including complement component 8, alpha (C8A), mannose binding lectin (MBL2), antithrombin III (SERPINC1), 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1), alcohol dehydrogenase 6 (ADH6), beta-ureidopropionase (UPB1) and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6). Our proposed methodology provides a swift assortment process for biomarker prioritization that eventually reduces the economic burden of experimental evaluation. Further dedicated validation studies of potential putative biomarkers on HCC patient blood samples are warranted. We hope that the use of such integrative secretome, interactome and miRNAs target filtration approach will accelerate the selection of high-priority biomarkers for other diseases as well, that are more amenable to downstream clinical validation experiments.
Highlights
Hepatocellular carcinoma (HCC), one of the most aggressive and devastating cancer, with an annual incidence of 0.6 million new cases, is the third leading cause of cancer related mortality worldwide [1, 2]
Our prioritization strategy has identified seven potential putative circulating protein biomarkers for HCC which are encoded by the target genes of HCC-specific liver deregulated and circulating miRNAs
Combination of pathological features and biomarkers with high sensitivity and specificity seems to be more practical for early diagnosis and prognostication of HCC
Summary
Hepatocellular carcinoma (HCC), one of the most aggressive and devastating cancer, with an annual incidence of 0.6 million new cases, is the third leading cause of cancer related mortality worldwide [1, 2]. Diagnosis and metastasis monitoring of HCC still remains a challenging task and is highly important [3]. In most of the cases, HCC patients die quickly because of the late diagnosis and rapid tumor progression. Hepatic resection and liver transplantation are the only potential curative treatments for HCC patients [3]. HCC recurrence occurs in 60–100% of the cases limiting the long-term survival of HCC patients. Biomarkers in blood or in other body fluids for screening, staging, prediction of recurrence, prognosis and monitoring of response to a therapy would be an important contribution to the management of patients with HCC
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