Abstract | OBJECTIVE: Due to the tissue specificity of the liver, long-term exposure to a high concentration of 27-hydroxycholesterol (27HC) is a special characteristic of the tumour microenvironment in hepatocellular carcinoma (HCC). However, what occurs after HCC cells are long-term exposure to 27HC and the molecular mechanisms involved remain largely unexamined. METHODS: A long-term 27HC-treated HepG2 cell line and the xenografts in nude mice were used as experimental models. Molecular mechanisms were investigated using bioinformatics analysis and molecular biological experiments. RESULTS: Here, we found that by inducing an increase in oxidative stress signalling, 27HC activated glucose-regulated protein 75 ( GRP75). On the one hand, GRP75 resulted in a change in the redox balance by regulating ROS generation and antioxidant system activity via affecting MMP, NRF2, HO-1, and NQO1 levels. On the other hand, GRP75 modified the metabolic reprogramming process by regulating key factors (HIF-1α, p-Akt, and c-myc) and glucose uptake, facilitating HCC cell growth in the inhospitable microenvironment. These two factors caused HCC cells to resist 27HC-induced cytotoxicity and attain multidrug resistance (MDR). CONCLUSIONS: Our present study not only identified 27HC, a characteristic component of the neoplastic microenvironment of HCC that causes MDR via GRP75 to regulate the redox balance and metabolic reprogramming, but also revealed that targeted intervention by the "switch"-like molecule GRP75 could reverse the effect of 27HC from cancer promotion to cytotoxicity in HCC, suggesting a new strategy for specific intervention of HCC.
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Authors | Ming Jin, Ye Yang, Yi Dai, Rong Cai, Liunan Wu, Yuwen Jiao, Zhan Zhang, Haojun Yang, Yan Zhou, Liming Tang, Lei Li, Yuan Li |
Journal | Cell biology and toxicology
(Cell Biol Toxicol)
Vol. 38
Issue 2
Pg. 311-324
(04 2022)
ISSN: 1573-6822 [Electronic] Netherlands |
PMID | 33880675
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2021. The Author(s), under exclusive licence to Springer Nature B.V. |
Chemical References |
- HSP70 Heat-Shock Proteins
- Hydroxycholesterols
- Membrane Proteins
- glucose-regulated proteins
- 27-hydroxycholesterol
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Topics |
- Animals
- Carcinoma, Hepatocellular
(genetics)
- Cell Line, Tumor
- Drug Resistance, Multiple
- Gene Expression Regulation, Neoplastic
- HSP70 Heat-Shock Proteins
- Humans
- Hydroxycholesterols
- Liver Neoplasms
(genetics)
- Membrane Proteins
- Mice
- Mice, Nude
- Oxidation-Reduction
- Tumor Microenvironment
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