Activation of AKT pathway by Nrf2/PDGFA feedback loop contributes to HCC progression
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Danyang Liu1,*, Yonglong Zhang2,*, Yingze Wei3, Guoyuan Liu1, Yufeng Liu1, Qiongmei Gao1, Liping Zou4, Wenjiao Zeng1, Nong Zhang1
1Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
2Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
3Department of Pathology, Tumor Hospital of Nantong, Nantong, China
4Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China
*These authors contributed equally to this work
Wenjiao Zeng, email: [email protected]
Nong Zhang, email: [email protected]
Keywords: Nrf2, PDGFA, hepatocellular carcinoma, AKT, tumorigenesis
Received: February 26, 2016 Accepted: August 24, 2016 Published: August 30, 2016
Nuclear factor erythroid-2-related factor 2 (Nrf2), a master transcription factor in the antioxidant response, has been found to be ubiquitously expressed in various cancer cells and in the regulation tumor proliferation, invasion, and chemoresistance activities. The regulatory roles of Nrf2 in controlling Hepatocellular carcinoma (HCC) progression remain unclear. In this study, we demonstrated that Nrf2 was significantly elevated in HCC cells and tissues and was correlated with poor prognosis of HCCs. Consistently, Nrf2 significantly promoted HCC cell growth both in vitro and in vivo. Further investigation suggested a novel association of Nrf2 with Platelet-Derived Growth Factor-A (PDGFA). Nrf2 promoted PDGFA transcription by recruiting specificity protein 1 (Sp1) to its promoter, resulting in increased activation of the AKT/p21 pathway and cell cycle progression of HCC cells. As a feedback loop, PDGFA enhanced Nrf2 expression and activation in an AKT dependent manner. In line with these findings, expression of Nrf2 and PDGFA were positively correlated in HCC tissues. Taken together, this study uncovers a novel mechanism of the Nrf2/PDGFA regulatory loop that is crucial for AKT-dependent HCC progression, and thereby provides potential targets for HCC therapy.
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