Qiao Yongxia, Zhang Xiao, Zhang Yue, Wang Yulan, Xu Yanfeng, Liu Xiangfan, Sun Fenyong, Wang Jiayi
School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
Diabetes. 2016 Mar;65(3):619-32. doi: 10.2337/db15-1057. Epub 2016 Jan 29.
Epidemiologic studies suggest that hepatocellular carcinoma (HCC) has a strong relationship with diabetes. However, the underlying molecular mechanisms still remain unclear. Here, we demonstrated that high glucose (HG), one of the main characteristics of diabetes, was capable of accelerating tumorigenesis in HCC cells. Advanced glycosylation end product-specific receptor (AGER) was identified as a stimulator during this process. Mechanistically, AGER activated a hexosamine biosynthetic pathway, leading to enhanced O-GlcNAcylation of target proteins. Notably, AGER was capable of increasing activity and stability of proto-oncoprotein c-Jun via O-GlcNAcylation of this protein at Ser73. Interestingly, c-Jun can conversely enhance AGER transcription. Thereby, a positive autoregulatory feedback loop that stimulates diabetic HCC was established. Finally, we found that AG490, an inhibitor of Janus kinase, has the ability to impair AGER expression and its functions in HCC cells. In conclusion, AGER and its functions to stimulate O-GlcNAcylation are important during liver tumorigenesis, when high blood glucose levels are inadequately controlled.
流行病学研究表明，肝细胞癌（HCC）与糖尿病密切相关。然而，其潜在的分子机制仍不清楚。在此，我们证明高血糖（HG）作为糖尿病的主要特征之一，能够加速肝癌细胞的肿瘤发生。晚期糖基化终产物特异性受体（AGER）在此过程中被确定为一种刺激因子。机制上，AGER激活了己糖胺生物合成途径，导致靶蛋白的O-连接N-乙酰葡糖胺化增强。值得注意的是，AGER能够通过在Ser73位点对原癌蛋白c-Jun进行O-连接N-乙酰葡糖胺化来增加其活性和稳定性。有趣的是，c-Jun反过来可以增强AGER的转录。由此，建立了一个刺激糖尿病性肝癌的正性自调节反馈环。最后，我们发现Janus激酶抑制剂AG490能够损害AGER在肝癌细胞中的表达及其功能。总之，当血糖水平控制不佳时，AGER及其刺激O-连接N-乙酰葡糖胺化的功能在肝脏肿瘤发生过程中很重要。
