CUL4B, NEDD4, and UGT1As involve in the TGF-β signalling in hepatocellular carcinoma

Ann Hepatol. 2016 Jul-Aug;15(4):568-76.

Abstract

Introduction and Aim. TGF-β signalling is involved in pathogenesis and progress of hepatocellular carcinoma (HCC). This bioinformatics study consequently aims to determine the underlying molecular mechanism of TGF- β activation in HCC cells.

Material and methods: Dataset GSE10393 was downloaded from Gene Expression Omnibus, including 2 Huh-7 (HCC cell line) samples treated by TGF- β (100 pmol/L, 48 h) and 2 untreated samples. Differentially expressed genes (DEGs) were screened using Limma package (false discovery rate < 0.05 and |log2 fold change| > 1.5), and then enrichment analyses of function, pathway, and disease were performed. In addition, protein-protein interaction (PPI) network was constructed based on the PPI data from multiple databases including INACT, MINT, BioGRID, UniProt, BIND, BindingDB, and SPIKE databases. Transcription factor (TF)-DEG pairs (Bonferroni adjusted p-value < 0.01) from ChEA database and DEG-DEG pairs were used to construct TF-DEG regulatory network. Furthermore, TF-pathway-DEG complex network was constructed by integrating DEG-DEG pairs, TF-DEG pairs, and DEG-pathway pairs.

Results: Totally, 209 DEGs and 30 TFs were identified. The DEGs were significantly enriched in adhesion-related functions. PPI network indicted hub genes such as CUL4B and NEDD4. According to the TF-DEG regulatory network, the two hub genes were targeted by SMAD2, SMAD3, and HNF4A. Besides, the 11 pathways in TF-pathway-DEG network were mainly enriched by UGT1A family and CYP3A7, which were predicted to be regulated by SMAD2, SMAD3, SOX2, TP63, and HNF4A.

Conclusions: TGF- β might influence biological processes of HCC cells via SMAD2/SMAD3-NEDD4, HNF4A-CUL4B/NEDD4, SOX2/TP63/HNF4A-CYP3A7, and SMAD2/SMAD3/SOX2/TP63/HNF4A-UGT1As regulatory pathways.

MeSH terms

  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Cell Adhesion / genetics
  • Cell Line, Tumor
  • Cullin Proteins / genetics*
  • Cullin Proteins / metabolism
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P-450 CYP3A / metabolism
  • Databases, Genetic
  • Endosomal Sorting Complexes Required for Transport / genetics*
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Gene Expression Profiling
  • Glucuronosyltransferase / genetics*
  • Glucuronosyltransferase / metabolism
  • Hepatocyte Nuclear Factor 4 / genetics
  • Hepatocyte Nuclear Factor 4 / metabolism
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Nedd4 Ubiquitin Protein Ligases
  • Protein Interaction Maps
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism
  • Signal Transduction / genetics
  • Smad2 Protein / genetics
  • Smad2 Protein / metabolism
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • CUL4B protein, human
  • Cullin Proteins
  • Endosomal Sorting Complexes Required for Transport
  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 4
  • SMAD2 protein, human
  • SMAD3 protein, human
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Smad2 Protein
  • Smad3 Protein
  • TP63 protein, human
  • Transcription Factors
  • Transforming Growth Factor beta
  • Tumor Suppressor Proteins
  • CYP3A7 protein, human
  • Cytochrome P-450 CYP3A
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4 protein, human
  • Ubiquitin-Protein Ligases
  • UGT1A1 enzyme
  • Glucuronosyltransferase