Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is becoming a critical risk of hepatocellular carcinoma (HCC). As both NAFLD and HCC are heterogeneous diseases, this study aims to identify the similarity between the subtypes of NAFLD and HCC based on gene modules. Methods Coexpressed gene modules were extracted for both NAFLD and HCC. The association between the coexpressed gene modules of NAFLD and HCC was evaluated by Fisher's exact test. The overlapping coexpressed gene module was validated in three independent human NAFLD datasets. Furthermore, the preserved gene module was assessed in four independent NAFLD mouse datasets. The significantly enriched motifs within the gene module were inferred from upstream sequences. Results Four coexpressed gene modules were extracted from NAFLD. Of the four coexpressed gene modules, one was significantly overlapping with a module of HCC. This overlapping gene module was regarded as the HCC-associated NAFLD gene module (HANM). Enrichment analysis of biological processes revealed inflammatory response in HANM. Specifically, within the inflammatory response biological process, IL-17, TNF-α, and NF-κB signaling pathways were enriched. HANM was found to be strongly or moderately conserved across four mouse NAFLD datasets. Motif analysis of the upstream genomic sequences of HANM revealed nine transcription factors (FLI1, NRF1, ZBTB33, ELK1, YY1, ZNF143, TAF1, SF1, and E2F1), of which three transcription factors (YY1, E2F1, and ZNF143) were significantly highly expressed in the NAFLD patients and exhibited survival significance in HCC. Conclusion This study demonstrated a robust way to identify the sharing gene signature between subtypes of NAFLD and HCC, which contributed to a comprehensive understanding of pathogenesis from NAFLD to HCC.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is becoming a critical risk of hepatocellular carcinoma (HCC)
Human datasets (GSE89632, GSE59045, GSE126848, and GSE83452) and mouse datasets (GSE13 7449, GSE128940, GSE114261, and GSE83596) were obtained from the Gene Expression Omnibus (GEO) database. e raw data were called and normalized with the Robust Multiarray Average (RMA) method and log2-transformed. e other HCC gene expression dataset was downloaded from TCGA and used in accordance with the publication guidelines of TCGA. e value of fragments per kilobase million was used as gene expression
To examine the characters of HCC-associated NAFLD gene module (HANM), we studied the enrichment of its upstream motifs through a web service, iRegulon [22]. e enriched motifs are shown in Figure 5(a). ose motifs were bound by the transcription factors including FLI1, NRF1, ZBTB33, ELK1, YY1, ZNF143, TAF1, SF1, and E2F1 (Table 1)
Summary
Nonalcoholic fatty liver disease (NAFLD) is becoming a critical risk of hepatocellular carcinoma (HCC). As both NAFLD and HCC are heterogeneous diseases, this study aims to identify the similarity between the subtypes of NAFLD and HCC based on gene modules. Coexpressed gene modules were extracted for both NAFLD and HCC. E association between the coexpressed gene modules of NAFLD and HCC was evaluated by Fisher’s exact test. E overlapping coexpressed gene module was validated in three independent human NAFLD datasets. Motif analysis of the upstream genomic sequences of HANM revealed nine transcription factors (FLI1, NRF1, ZBTB33, ELK1, YY1, ZNF143, TAF1, SF1, and E2F1), of which three transcription factors (YY1, E2F1, and ZNF143) were significantly highly expressed in the NAFLD patients and exhibited survival significance in HCC. Other studies from Germany [8], Italy [9], and Japan [10] have reported that 41.7–49% of HCC patients without cirrhotic background were related to NAFLD. us, it is urgent to understand the associated mechanisms behind them
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