Hedgehog signalling mediates drug resistance through targeting TAP1 in hepatocellular carcinoma

J Cell Mol Med. 2020 Apr;24(7):4298-4311. doi: 10.1111/jcmm.15090. Epub 2020 Feb 28.


Multidrug resistance is one of the reasons for low survival of advanced hepatocellular carcinoma (HCC). Our previous studies indicate that the hedgehog signalling is involved in hepatic carcinogenesis, metastasis and chemo-resistance. The present study aims to uncover molecular mechanisms underlying hepatoma chemo-resistance. TAP1 and GLI1/2 gene expression was assessed in both poorly differentiated hepatoma cells and HCC specimens. Potential GLI-binding site in the TAP1 promoter sequence was validated by molecular assays. Approximately 75% HCC specimens exhibited an elevated expression of hedgehog GLI1 transcription factor compared with adjacent liver tissue. Both GLI1/2 and TAP1 protein levels were significantly elevated in poorly differentiated hepatoma cells. Both Huh-7-trans and Huh-7-DN displayed more karyotypic abnormalities and differential gene expression profiles than their native Huh-7 cells. Sensitivity to Sorafenib, doxorubicin and cisplatin was remarkably improved after either GLI1 or TAP1 gene was inhibited by an RNAi approach or by a specific GLI1/2 inhibitor, GANT61. Further experiments confirmed that hedgehog transcription factor GLI1/2 binds to the TAP1 promoter, indicating that TAP1 is one of GLI1/2 target genes. In conclusion, TAP1 is under direct transcriptional control of the hedgehog signalling. Targeting hedgehog signalling confers a novel insight into alleviating drug resistance in the treatment of refractory HCC.

Keywords: GANT61; TAP1; chemo-resistance; hedgehog signalling; hepatocellular carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 2 / genetics*
  • Carcinogenesis / drug effects
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Hedgehog Proteins / antagonists & inhibitors
  • Hedgehog Proteins / genetics
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology
  • Male
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / genetics
  • Promoter Regions, Genetic / genetics
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • Signal Transduction
  • Zinc Finger Protein GLI1 / antagonists & inhibitors*
  • Zinc Finger Protein GLI1 / genetics
  • Zinc Finger Protein Gli2 / antagonists & inhibitors*
  • Zinc Finger Protein Gli2 / genetics


  • ATP Binding Cassette Transporter, Subfamily B, Member 2
  • DNA-Binding Proteins
  • GANT 61
  • GLI1 protein, human
  • GLI2 protein, human
  • Hedgehog Proteins
  • Nuclear Proteins
  • Pyridines
  • Pyrimidines
  • TAP1 protein, human
  • Zinc Finger Protein GLI1
  • Zinc Finger Protein Gli2