title: CUL4B, NEDD4, and UGT1As involve in the TGF-β signalling in hepatocellular carcinoma.
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.
  
  
  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.
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin 150081, Heilongjiang Province, China.
authors.forename: Zhaowei
authors.initials: Z
authors.lastname: Qu
authors.affiliation: Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China.
authors.forename: Di
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin 150081, Heilongjiang Province, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Xu
authors.affiliation: Operating Room, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China.
authors.forename: Rujia
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin 150081, Heilongjiang Province, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin 150081, Heilongjiang Province, China.
authors.forename: Chengming
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin 150081, Heilongjiang Province, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Dong
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin 150081, Heilongjiang Province, China.
authors.forename: Yubao
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D030541:Databases, Genetic; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D000075702:Nedd4 Ubiquitin Protein Ligases; D060066:Protein Interaction Maps; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D000099148:UGT1A1 Enzyme
chemical_list: D044842:Cullin Proteins; D051544:Cytochrome P-450 CYP3A; D056827:Endosomal Sorting Complexes Required for Transport; D014453:Glucuronosyltransferase; D051557:Hepatocyte Nuclear Factor 4; D000075702:Nedd4 Ubiquitin Protein Ligases; D055748:SOXB1 Transcription Factors; D051899:Smad2 Protein; D051900:Smad3 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D000099148:UGT1A1 Enzyme; C517832:CUL4B protein, human; C496592:HNF4A protein, human; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C527782:SOX2 protein, human; C115051:TP63 protein, human; C103123:CYP3A7 protein, human; C000618483:Nedd4 protein, human