title: Activation of AKT pathway by Nrf2/PDGFA feedback loop contributes to HCC progression.
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.
authors: Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors: Danyang
authors: D
authors: Liu
authors: Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors: Yonglong
authors: Y
authors: Zhang
authors: Department of Pathology, Tumor Hospital of Nantong, Nantong, China.
authors: Yingze
authors: Y
authors: Wei
authors: Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors: Guoyuan
authors: G
authors: Liu
authors: Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors: Yufeng
authors: Y
authors: Liu
authors: Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors: Qiongmei
authors: Q
authors: Gao
authors: Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China.
authors: Liping
authors: L
authors: Zou
authors: Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors: Wenjiao
authors: W
authors: Zeng
authors: Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors: Nong
authors: N
authors: Zhang
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D025461:Feedback, Physiological; D005500:Follow-Up Studies; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; Nrf2; PDGFA; hepatocellular carcinoma; tumorigenesis