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.

中文翻译：

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27-羟基胆固醇是 HCC 肿瘤微环境中的一个特定因素，它通过 GRP75 调节氧化还原平衡和代谢重编程引起 MDR

客观的

由于肝脏的组织特异性，长期暴露于高浓度的 27-羟基胆固醇 (27HC) 是肝细胞癌 (HCC) 肿瘤微环境的一个特殊特征。然而，HCC 细胞长期暴露于 27HC 后发生的情况，其所涉及的分子机制在很大程度上仍未得到检验。

方法

将长期 27HC 处理的 HepG2 细胞系和裸鼠异种移植物用作实验模型。使用生物信息学分析和分子生物学实验研究了分子机制。

结果

在这里，我们发现通过诱导氧化应激信号的增加，27HC 激活了葡萄糖调节蛋白 75 (GRP75)。一方面，GRP75 通过影响 MMP、NRF2、HO-1 和 NQO1 水平来调节 ROS 生成和抗氧化系统活性，从而导致氧化还原平衡发生变化。另一方面，GRP75 通过调节关键因子（HIF-1α、p-Akt 和 c-myc）和葡萄糖摄取来改变代谢重编程过程，促进 HCC 细胞在恶劣的微环境中生长。这两个因素导致HCC细胞抵抗27HC诱导的细胞毒性并获得多药耐药性（MDR）。

结论

我们目前的研究不仅确定了 HCC 肿瘤微环境的特征成分 27HC，它通过 GRP75 导致 MDR 调节氧化还原平衡和代谢重编程，而且还揭示了“开关”样分子 GRP75 的靶向干预可以逆转这种效应27HC 从癌症促进到 HCC 的细胞毒性，提示了一种针对 HCC 的特异性干预的新策略。