ABSTRACT

A cornucopia of literatures has characterized the involvement of a host of functional molecules in liver cancer. Herein, according to online datasets, we found that cytochrome P450 family 2 subfamily C member 8 (CYP2C8) was downregulated in liver cancer, and high CYP2C8 expression was associated with favorable overall survival. Lower levels of CYP2C8 were confirmed in liver cancer cells. CYP2C8 overexpression efficiently attenuated liver cancer cell proliferation and promoted apoptosis. We then discovered that miR-382-3p directly targeted CYP2C8 to inhibit its expression in liver cancer cells based on bioinformatic prediction and experimental confirmation. Moreover, a cytoplasmic long noncoding RNA (lncRNA), growth arrest-specific 5 (GAS5), sponged and down-regulated miR-382-3p, thus positively modulating CYP2C8 expression. Rescue assays indicated that GAS5 overexpression gave rise to decreased proliferation and increased apoptosis of liver cancer cells, while CYP2C8 knockdown counteracted GAS5-mediated anti-carcinogenic effects. In summary, our work offered a solid experimental foundation for understanding the functional role of CYP2C8 and the mechanism of GAS5/miR-382-3p/CYP2C8 axis in cell proliferation and apoptosis of liver cancer.

摘要

大量文献描述了许多功能分子参与肝癌的特征。在此，根据在线数据集，我们发现细胞色素 P450 家族 2 亚家族 C 成员 8 (CYP2C8) 在肝癌中下调，并且 CYP2C8 高表达与有利的总生存期相关。在肝癌细胞中证实了较低水平的CYP2C8。CYP2C8 过表达有效减弱肝癌细胞增殖并促进细胞凋亡。然后我们发现，基于生物信息学预测和实验证实，miR-382-3p 直接靶向 CYP2C8 以抑制其在肝癌细胞中的表达。此外，细胞质长链非编码 RNA (lncRNA)、生长停滞特异性 5 (GAS5) 海绵化并下调 miR-382-3p，从而正向调节 CYP2C8 表达。救援试验表明，GAS5 过表达导致肝癌细胞增殖减少和凋亡增加，而 CYP2C8 敲低抵消了 GAS5 介导的抗癌作用。总之，我们的工作为理解CYP2C8的功能作用和GAS5/miR-382-3p/CYP2C8轴在肝癌细胞增殖和凋亡中的作用机制提供了坚实的实验基础。