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Hedgehog signalling mediates drug resistance through targeting TAP1 in hepatocellular carcinoma

Xiao-Tian Zhou1, Jia Ding2, Hui-Yan Li1

  • 1MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.

Journal of Cellular and Molecular Medicine
|February 29, 2020
PubMed

Insights

Targeting the hedgehog signaling pathway can overcome multidrug resistance in advanced hepatocellular carcinoma (HCC). Inhibiting GLI1/2 or TAP1 gene expression significantly improved chemotherapy sensitivity in HCC cells, offering new treatment insights.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Multidrug resistance significantly reduces survival rates in advanced hepatocellular carcinoma (HCC).
  • Hedgehog signaling is implicated in HCC development, metastasis, and chemoresistance.
  • Understanding chemoresistance mechanisms is crucial for improving HCC patient outcomes.

Purpose of the Study:

  • To elucidate the molecular mechanisms driving chemoresistance in hepatoma.
  • To investigate the role of the hedgehog signaling pathway and TAP1 in HCC chemoresistance.

Main Methods:

  • Assessed GLI1/2 and TAP1 gene expression in HCC cells and specimens.
  • Validated the GLI-binding site in the TAP1 promoter using molecular assays.
  • Utilized RNA interference (RNAi) and a GLI1/2 inhibitor (GANT61) to modulate gene expression and assess drug sensitivity.

Main Results:

  • Elevated GLI1 expression was observed in approximately 75% of HCC specimens.
  • Both GLI1/2 and TAP1 protein levels were significantly higher in poorly differentiated hepatoma cells.
  • Inhibition of GLI1 or TAP1 markedly enhanced sensitivity to Sorafenib, doxorubicin, and cisplatin.
  • Confirmed direct binding of GLI1/2 to the TAP1 promoter, identifying TAP1 as a GLI1/2 target gene.

Conclusions:

  • TAP1 is directly transcriptionally regulated by the hedgehog signaling pathway.
  • Targeting hedgehog signaling presents a novel strategy for overcoming drug resistance in refractory HCC.
  • This research provides a deeper understanding of chemoresistance mechanisms in HCC, paving the way for improved therapeutic approaches.
Keywords:
GANT61TAP1chemo-resistancehedgehog signallinghepatocellular carcinoma

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