Insights into the etiology-associated gene regulatory networks in hepatocellular carcinoma from The Cancer Genome Atlas
Veerabrahma Pratap Seshachalam
Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Center Singapore, Singapore
Veerabrahma Pratap Seshachalam and Karthik Sekar contributed equally to this work.Search for more papers by this authorKarthik Sekar
Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Center Singapore, Singapore
Veerabrahma Pratap Seshachalam and Karthik Sekar contributed equally to this work.Search for more papers by this authorCorresponding Author
Kam M Hui
Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Center Singapore, Singapore
Institute of Molecular and Cell Biology, A*STAR, Singapore
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Correspondence
Kam M Hui, Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Center Singapore, 11 Hospital Drive, National Cancer Centre, 169610 Singapore.
Email: [email protected]
Search for more papers by this authorVeerabrahma Pratap Seshachalam
Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Center Singapore, Singapore
Veerabrahma Pratap Seshachalam and Karthik Sekar contributed equally to this work.Search for more papers by this authorKarthik Sekar
Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Center Singapore, Singapore
Veerabrahma Pratap Seshachalam and Karthik Sekar contributed equally to this work.Search for more papers by this authorCorresponding Author
Kam M Hui
Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Center Singapore, Singapore
Institute of Molecular and Cell Biology, A*STAR, Singapore
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Correspondence
Kam M Hui, Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Center Singapore, 11 Hospital Drive, National Cancer Centre, 169610 Singapore.
Email: [email protected]
Search for more papers by this authorAbstract
Background and Aim
Hepatitis B virus (HBV), hepatitis C virus, alcohol consumption, and non-alcoholic fatty liver disease are the major known risk factors for hepatocellular carcinoma (HCC). There have been very few studies comparing the underlying biological mechanisms associated with the different etiologies of HCC. In this study, we hypothesized the existence of different regulatory networks associated with different liver disease etiologies involved in hepatocarcinogenesis.
Methods
Using upstream regulatory analysis tool in ingenuity pathway analysis software, upstream regulators (URs) were predicted using differential expressed genes for HCC to facilitate the interrogation of global gene regulation.
Results
Analysis of regulatory networks for HBV HCC revealed E2F1 as activated UR, regulating genes involved in cell cycle and DNA replication, and HNF4A and HNF1A as inhibited UR. In hepatitis C virus HCC, interferon-γ, involved in cellular movement and signaling, was activated, while IL1RN, mitogen-activated protein kinase 1 involved in interleukin 22 signaling and immune response, was inhibited. In alcohol consumption HCC, ERBB2 involved in inflammatory response and cellular movement was activated, whereas HNF4A and NUPR1 were inhibited. For HCC derived from non-alcoholic fatty liver disease, miR-1249-5p was activated, and NUPR1 involved in cell cycle and apoptosis was inhibited. The prognostic value of representative genes identified in the regulatory networks for HBV HCC can be further validated by an independent HBV HCC dataset established in our laboratory with survival data.
Conclusions
Our study identified functionally distinct candidate URs for HCC developed from different etiologic risk factors. Further functional validation studies of these regulatory networks could facilitate the management of HCC towards personalized medicine.
Supporting Information
| Filename | Description |
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| jgh_14262-sup-0001-supplementary materials.zipapplication/x-zip-compressed, 156.4 KB |
Table S1. Significant URs for HBV B HCC. Full list of URs are provided along with the symbols and counts for the target genes. Table S2. Significant URs for HCV C HCC. Table S3. Significant URs for AC HCC. Table S4. Significant URs for NAFLD HCC. Figure S1. Venn diagram showing overlapping DEGs from TCGA RNAseq and Microarrays for HBV, HCV, AC HCC. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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