Hedgehog Signal Inhibitor GANT61 Inhibits the Malignant Behavior of Undifferentiated Hepatocellular Carcinoma Cells by Targeting Non-Canonical GLI Signaling

Autor: Ryuya Ohashi, Keita Kanki, Kyoko Naito, Kensuke Harada
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Pyridines
Malignant transformation
lcsh:Chemistry
0302 clinical medicine
non-canonical Hedgehog-GLI signaling
lcsh:QH301-705.5
Spectroscopy
MEK inhibitor
Liver Neoplasms
Nuclear Proteins
General Medicine
Hep G2 Cells
hepatocellular carcinoma
Computer Science Applications
Up-Regulation
Gene Expression Regulation
Neoplastic
030220 oncology & carcinogenesis
embryonic structures
medicine.drug
Signal Transduction
Sorafenib
Carcinoma
Hepatocellular
Epithelial-Mesenchymal Transition
Cell Survival
Biology
Zinc Finger Protein Gli2
Zinc Finger Protein GLI1
Catalysis
Article
Inorganic Chemistry
03 medical and health sciences
GLI1
GLI2
Cell Line
Tumor
medicine
Humans
Physical and Theoretical Chemistry
GANT61
Molecular Biology
Cell Proliferation
Organic Chemistry
CD44
030104 developmental biology
Pyrimidines
lcsh:Biology (General)
lcsh:QD1-999
BMI1
Cancer cell
Cancer research
biology.protein
Zdroj: International Journal of Molecular Sciences
Volume 21
Issue 9
International Journal of Molecular Sciences, Vol 21, Iss 3126, p 3126 (2020)
ISSN: 1422-0067
DOI: 10.3390/ijms21093126
Popis: The Hedgehog (HH)&ndash
GLI pathway plays an important role in cell dedifferentiation and is therefore pivotally involved in the malignant transformation of cancer cells. GANT61, a selective inhibitor of GLI1 and GLI2, was reported as a promising treatment for cancer in various tissues
however, the biological impact of GANT61 in hepatocellular carcinoma (HCC), especially in undifferentiated HCC cells, remains unclear. In this study, we investigated the antitumor effect of GANT61 using two undifferentiated hepatoma cell lines: HLE and HLF. Quantitative PCR and RT-PCR analyses revealed that these cells express GLI transcripts, showing mesenchymal phenotypes characterized by the loss of epithelial and hepatic markers and specific expression of epithelial&ndash
mesenchymal transition (EMT)-related genes. GANT61 significantly reduced the proliferation and cell viability after drug treatment using 5-FU and Mitomycin C. We showed that GLI transcript levels were down-regulated by the MEK inhibitor U0126 and the Raf inhibitor sorafenib, suggesting that non-canonical signaling including the Ras&ndash
Raf&ndash
MEK&ndash
ERK pathway is involved. Sphere formation and migration were significantly decreased by GANT61 treatment, and it is suggested that the underlying molecular mechanisms are the down-regulation of stemness-related genes (Oct4, Bmi1, CD44, and ALDH) and the EMT-related gene Snail1. The data presented here showed that direct inhibition of GLI might be beneficial for the treatment of dedifferentiated HCC.
Databáze: OpenAIRE
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