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.

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.