Activation of AKT pathway by Nrf2/PDGFA feedback loop contributes to HCC progression

// Danyang Liu 1, * , Yonglong Zhang 2, * , Yingze Wei 3 , Guoyuan Liu 1 , Yufeng Liu 1 , Qiongmei Gao 1 , Liping Zou 4 , Wenjiao Zeng 1 , Nong Zhang 1 1 Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China 2 Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China 3 Department of Pathology, Tumor Hospital of Nantong, Nantong, China 4 Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China * These authors contributed equally to this work Correspondence to: Wenjiao Zeng, email: wjzeng@fudan.edu.cn Nong Zhang, email: nzhang@fudan.edu.cn Keywords: Nrf2, PDGFA, hepatocellular carcinoma, AKT, tumorigenesis Received: February 26, 2016      Accepted: August 24, 2016      Published: August 30, 2016 ABSTRACT 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.