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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Funding
This work was supported by the National Natural Science Foundation of China (81961160708 to YL; 81973096 to LL); the Natural Science Foundation of Jiangsu Province (BK20181155 to LT); the “Qing Lan” Project Funded by Jiangsu Province (to YL); the Project Funded by Jiangsu Postgraduate Research and Innovation Plan (SJCX19-0316 to MJ); the Project Funded by Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine (JX21817902/006 to YL); and the Major Projects of Science and Technology Development Fund of Nanjing Medical University (NMUD2019008 to YL).
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YL, LL, and LT conceived the research. MJ, YD, and YJ performed cell experiments. YY and ZZ performed the in vivo experiments. RC, LW, and HY carried out the bioinformatics analysis. YZ and YY analyzed the data. MJ, YD, and YY drafted the manuscript. All the authors have read and approved the final version of the manuscript. MJ, YY, and YD contributed equally to this work.
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Highlights
1. Long-term exposure to 27HC caused MDR in HCC cells.
2. Redox balance and metabolic reprogramming were two important neoplastic biological behaviours in 27HC-induced MDR.
3. Identified GRP75 as a “switch”-like molecule, facilitating 27HC-induced MDR.
4. Knockdown of GRP75 reversed the roles of 27HC from cancer promotion to HCC cytotoxicity, suggesting a new idea of HCC intervention.
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Jin, M., Yang, Y., Dai, Y. et al. 27-Hydroxycholesterol is a specific factor in the neoplastic microenvironment of HCC that causes MDR via GRP75 regulation of the redox balance and metabolic reprogramming. Cell Biol Toxicol 38, 311–324 (2022). https://doi.org/10.1007/s10565-021-09607-y
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DOI: https://doi.org/10.1007/s10565-021-09607-y