Research Papers:

Aldose reductase interacts with AKT1 to augment hepatic AKT/ mTOR signaling and promote hepatocarcinogenesis

Jia-Xing Zhao, Ya-Wei Yuan, Cheng-Fu Cai, Dong-Yan Shen, Mao-Li Chen, Feng Ye, Yan-Jun Mi, Qi-Cong Luo, Wang-Yu Cai, Wei Zhang, Ying Long, Yong Zeng, Guo-Dong Ye and Shu-Yu Yang _

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Oncotarget. 2017; 8:66987-67000. https://doi.org/10.18632/oncotarget.17791

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Jia-Xing Zhao1,*, Ya-Wei Yuan2,*, Cheng-Fu Cai3,*, Dong-Yan Shen3, Mao-Li Chen4, Feng Ye3, Yan-Jun Mi3, Qi-Cong Luo3, Wang-Yu Cai5, Wei Zhang3, Ying Long6, Yong Zeng6, Guo-Dong Ye3 and Shu-Yu Yang3

1State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361002, China

2State Key Laboratory of Marine Environmental Science, College of Ocean and Earth Sciences, Xiamen University, Xiamen, Fujian, 361002, China

3The First Affiliated Hospital, Medical College, Xiamen University, Xiamen, Fujian, 361003, China

4School of Pharmaceutical Science, Xiamen University, Xiamen, Fujian, 361003, China

5Medical College, Xiamen University, Xiamen, Fujian, 361003, China

6Translational Medicine Center, Hunan Cancer Hospital, Changsha, Hunan, 410013, China

*These authors contributed equally to this work

Correspondence to:

Shu-Yu Yang, email: [email protected]

Guo-Dong Ye, email: [email protected]

Keywords: aldose reductase, AKT/mTOR signaling, hepatocellular carcinoma

Received: November 22, 2016     Accepted: April 25, 2017     Published: May 10, 2017


Marked up-regulation of aldose reductase (AR) is reportedly associated with the development of hepatocellular carcinoma (HCC). We investigated how aberrantly overexpressed AR might promote oncogenic transformation in liver cells and tissues. We found that overexpressed AR interacted with the kinase domain of AKT1 to increase AKT/mTOR signaling. In both cultured liver cancer cells and liver tissues in DEN-induced transgenic HCC model mice, we observed that AR overexpression-induced AKT/mTOR signaling tended to enhance lactate formation and hepatic inflammation to enhance hepatocarcinogenesis. Conversely, AR knockdown suppressed lactate formation and inflammation. Using cultured liver cancer cells, we also demonstrated that AKT1 was essential for AR-induced dysregulation of AKT/mTOR signaling, metabolic reprogramming, antioxidant defense, and inflammatory responses. These findings suggest that aberrantly overexpressed/over-activated hepatic AR promotes HCC development at least in part by interacting with oncogenic AKT1 to augment AKT/mTOR signaling. Inhibition of AR and/or AKT1 might serve as an effective strategy for the prevention and therapy of liver cancer.

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