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

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 cont...

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Bibliographic Details
Published in:Oncotarget 2016-10, Vol.7 (40), p.65389-65402
Main Authors: Liu, Danyang, Zhang, Yonglong, Wei, Yingze, Liu, Guoyuan, Liu, Yufeng, Gao, Qiongmei, Zou, Liping, Zeng, Wenjiao, Zhang, Nong
Format: Article
Language:English
Subjects:
Animals
Carcinogenesis - metabolism
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - mortality
Carcinoma, Hepatocellular - pathology
Cell Cycle
Cell Proliferation
Feedback, Physiological
Follow-Up Studies
Hep G2 Cells
Humans
Liver Neoplasms - metabolism
Liver Neoplasms - mortality
Liver Neoplasms - pathology
Male
Mice
Mice, Inbred BALB C
Mice, Nude
NF-E2-Related Factor 2 - metabolism
Platelet-Derived Growth Factor - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Research Paper
Signal Transduction
Survival Analysis
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.11700