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Global gene expression profiling reveals SPINK1 as a potential hepatocellular carcinoma marker.

ABSTRACT: BACKGROUND:Liver cirrhosis is the most important risk factor for hepatocellular carcinoma (HCC) but the role of liver disease aetiology in cancer development remains under-explored. We investigated global gene expression profiles from HCC arising in different liver diseases to test whether HCC development is driven by expression of common or different genes, which could provide new diagnostic markers or therapeutic targets. METHODOLOGY AND PRINCIPAL FINDINGS:Global gene expression profiling was performed for 4 normal (control) livers as well as 8 background liver and 7 HCC from 3 patients with hereditary haemochromatosis (HH) undergoing surgery. In order to investigate different disease phenotypes causing HCC, the data were compared with public microarray repositories for gene expression in normal liver, hepatitis C virus (HCV) cirrhosis, HCV-related HCC (HCV-HCC), hepatitis B virus (HBV) cirrhosis and HBV-related HCC (HBV-HCC). Principal component analysis and differential gene expression analysis were carried out using R Bioconductor. Liver disease-specific and shared gene lists were created and genes identified as highly expressed in hereditary haemochromatosis HCC (HH-HCC) were validated using quantitative RT-PCR. Selected genes were investigated further using immunohistochemistry in 86 HCC arising in liver disorders with varied aetiology. Using a 2-fold cut-off, 9 genes were highly expressed in all HCC, 11 in HH-HCC, 270 in HBV-HCC and 9 in HCV-HCC. Six genes identified by microarray as highly expressed in HH-HCC were confirmed by RT qPCR. Serine peptidase inhibitor, Kazal type 1 (SPINK1) mRNA was very highly expressed in HH-HCC (median fold change 2291, p?=?0.0072) and was detected by immunohistochemistry in 91% of HH-HCC, 0% of HH-related cirrhotic or dysplastic nodules and 79% of mixed-aetiology HCC. CONCLUSION:HCC, arising from diverse backgrounds, uniformly over-express a small set of genes. SPINK1, a secretory trypsin inhibitor, demonstrated potential as a diagnostic HCC marker and should be evaluated in future studies.

SUBMITTER: Marshall A

PROVIDER: S-EPMC3601070 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Global gene expression profiling reveals SPINK1 as a potential hepatocellular carcinoma marker.

Marshall Aileen A Lukk Margus M Kutter Claudia C Davies Susan S Alexander Graeme G Odom Duncan T DT

PloS one 20130318 3

<h4>Background</h4>Liver cirrhosis is the most important risk factor for hepatocellular carcinoma (HCC) but the role of liver disease aetiology in cancer development remains under-explored. We investigated global gene expression profiles from HCC arising in different liver diseases to test whether HCC development is driven by expression of common or different genes, which could provide new diagnostic markers or therapeutic targets.<h4>Methodology and principal findings</h4>Global gene expression ...[more]

PMID: 23527199

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Project description:Objective: The study aimed to elucidate the significance of CLEC4G, CAMK2β, SLC22A1, CBFA2T3, and STAB2 in the prognosis of hepatocellular carcinoma (HCC) patients and their associated molecular biological characteristics. Additionally, the research sought to identify new potential biomarkers with therapeutic and diagnostic relevance for clinical applications. Methods and Materials: We utilized a publicly available high throughput phosphoproteomics and proteomics data set of HCC to focus on the analysis of 12 downregulated phosphoproteins in HCC. Our approach integrates bioinformatic analysis with pathway analysis, encompassing gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and the construction of a protein-protein interaction (PPI) network. Results: In total, we quantified 11547 phosphorylation sites associated with 4043 phosphoproteins from a cohort of 159 HCC patients. Within this extensive data set, our specific focus was on 19 phosphorylation sites displaying significant downregulation (log2 FC ≤ -2 with p-values < 0.0001). Remarkably, our investigation revealed distinct pathways exhibiting differential regulation across multiple dimensions, including the genomic, transcriptomic, proteomic, and phosphoproteomic levels. These pathways encompass a wide range of critical cellular processes, including cellular component organization, cell cycle control, signaling pathways, transcriptional and translational control, and metabolism. Furthermore, our bioinformatics analysis unveiled noteworthy insights into the subcellular localizations, biological processes, and molecular functions associated with these proteins and phosphoproteins. Within the context of the PPI network, we identified 12 key genes CLEC4G, STAB2, ADH1A, ADH1B, CAMK2B, ADH4, CHGB, PYGL, ADH1C, AKAP12, CBFA2T3, and SLC22A1 as the top highly interconnected hub genes. Conclusions: The findings related to CLEC4G, ADH1B, SLC22A1, CAMK2β, CBFA2T3, and STAB2 indicate their reduced expression in HCC, which is associated with an unfavorable prognosis. Furthermore, the results of KEGG and GO pathway analyses suggest that these genes may impact liver cancer by engaging various targets and pathways, ultimately promoting the progression of hepatocellular carcinoma. These results underscore the significant potential of CLEC4G, ADH1B, SLC22A1, CAMK2β, CBFA2T3, and STAB2 as key contributors to HCC development and advancement. This insight holds promise for identifying therapeutic targets and charting research avenues to enhance our understanding of the intricate molecular mechanisms underlying hepatocellular carcinoma.

Project description:BackgroundComplex molecular events lead to development and progression of liver cirrhosis to HCC. Differentially expressed nuclear membrane associated proteins are responsible for the functional and structural alteration during the progression from cirrhosis to carcinoma. Although alterations/ post translational modifications in protein expression have been extensively quantified, complementary analysis of nuclear membrane proteome changes have been limited. Deciphering the molecular mechanism that differentiate between normal and disease state may lead to identification of biomarkers for carcinoma.ResultsMany proteins displayed differential expression when nuclear membrane proteome of hepatocellular carcinoma (HCC), fibrotic liver, and HepG2 cell line were assessed using 2-DE and ESI-Q-TOF MS/MS. From the down regulated set in HCC, we have identified for the first time a 15 KDa cytochrome b5A (CYB5A), ATP synthase subunit delta (ATPD) and Hemoglobin subunit beta (HBB) with 11, 5 and 22 peptide matches respectively. Furthermore, nitrosylation studies with S-nitrosocysteine followed by immunoblotting with anti SNO-cysteine demonstrated a novel and biologically relevant post translational modification of thiols of CYB5A in HCC specimens only. Immunofluorescence images demonstrated increased protein S-nitrosylation signals in the tumor cells and fibrotic region of HCC tissues. The two other nuclear membrane proteins which were only found to be nitrosylated in case of HCC were up regulated ATP synthase subunit beta (ATPB) and down regulated HBB. The decrease in expression of CYB5A in HCC suggests their possible role in disease progression. Further insight of the functional association of the identified proteins was obtained through KEGG/ REACTOME pathway analysis databases. String 8.3 interaction network shows strong interactions with proteins at high confidence score, which is helpful in characterization of functional abnormalities that may be a causative factor of liver pathology.ConclusionThese findings may have broader implications for understanding the mechanism of development of carcinoma. However, large scale studies will be required for further verification of their critical role in development and progression of HCC.

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Global gene expression profiling reveals SPINK1 as a potential hepatocellular carcinoma marker.

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Global gene expression profiling reveals SPINK1 as a potential hepatocellular carcinoma marker.

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