The GNAQ T96S Mutation Affects Cell Signaling and Enhances the Oncogenic Properties of Hepatocellular Carcinoma

Int J Mol Sci. 2021 Mar 23;22(6):3284. doi: 10.3390/ijms22063284.


Hepatocellular carcinoma (HCC), the most common malignant tumor in the liver, grows and metastasizes rapidly. Despite advances in treatment modalities, the five-year survival rate of HCC remains less than 30%. We sought genetic mutations that may affect the oncogenic properties of HCC, using The Cancer Genome Atlas (TCGA) data analysis. We found that the GNAQ T96S mutation (threonine 96 to serine alteration of the Gαq protein) was present in 12 out of 373 HCC patients (3.2%). To examine the effect of the GNAQ T96S mutation on HCC, we transfected the SK-Hep-1 cell line with the wild-type or the mutant GNAQ T96S expression vector. Transfection with the wild-type GNAQ expression vector enhanced anchorage-independent growth, migration, and the MAPK pathways in the SK-Hep-1 cells compared to control vector transfection. Moreover, cell proliferation, anchorage-independent growth, migration, and the MAPK pathways were further enhanced in the SK-Hep-1 cells transfected with the GNAQ T96S expression vector compared to the wild-type GNAQ-transfected cells. In silico structural analysis shows that the substitution of the GNAQ amino acid threonine 96 with a serine may destabilize the interaction between the regulator of G protein signaling (RGS) protein and GNAQ. This may reduce the inhibitory effect of RGS on GNAQ signaling, enhancing the GNAQ signaling pathway. Single nucleotide polymorphism (SNP) genotyping analysis for Korean HCC patients shows that the GNAQ T96S mutation was found in only one of the 456 patients (0.22%). Our data suggest that the GNAQ T96S hotspot mutation may play an oncogenic role in HCC by potentiating the GNAQ signal transduction pathway.

Keywords: guanine nucleotide-binding protein G(q) subunit alpha; helical domain; hepatocellular carcinoma; mitogen-activated protein kinase (MAPK) signaling; somatic mutation.

MeSH terms

  • Alleles
  • Amino Acid Substitution
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Movement / genetics
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Disease Susceptibility
  • GTP-Binding Protein alpha Subunits, Gq-G11 / chemistry
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Gene Expression
  • Genotype
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • MAP Kinase Signaling System
  • Models, Molecular
  • Mutation*
  • Oncogenes
  • Protein Conformation
  • Signal Transduction*
  • Structure-Activity Relationship


  • GNAQ protein, human
  • GTP-Binding Protein alpha Subunits, Gq-G11