Oncogenic transformation of mesenchymal stem cells decreases Nrf2 expression favoring in vivo tumor growth and poorer survivalReport as inadecuate




Oncogenic transformation of mesenchymal stem cells decreases Nrf2 expression favoring in vivo tumor growth and poorer survival - Download this document for free, or read online. Document in PDF available to download.

Molecular Cancer

, 13:20

First Online: 03 February 2014Received: 01 August 2013Accepted: 27 January 2014DOI: 10.1186-1476-4598-13-20

Cite this article as: Funes, J.M., Henderson, S., Kaufman, R. et al. Mol Cancer 2014 13: 20. doi:10.1186-1476-4598-13-20

Abstract

BackgroundThe transcription factor Nrf2 is a key regulator of the cellular antioxidant response, and its activation by chemoprotective agents has been proposed as a potential strategy to prevent cancer. However, activating mutations in the Nrf2 pathway have been found to promote tumorigenesis in certain models. Therefore, the role of Nrf2 in cancer remains contentious.

MethodsWe employed a well-characterized model of stepwise human mesenchymal stem cell MSC transformation and breast cancer cell lines to investigate oxidative stress and the role of Nrf2 during tumorigenesis. The Nrf2 pathway was studied by microarray analyses, qRT-PCR, and western-blotting. To assess the contribution of Nrf2 to transformation, we established tumor xenografts with transformed MSC expressing Nrf2 n = 6 mice per group. Expression and survival data for Nrf2 in different cancers were obtained from GEO and TCGA databases. All statistical tests were two-sided.

ResultsWe found an accumulation of reactive oxygen species during MSC transformation that correlated with the transcriptional down-regulation of antioxidants and Nrf2-downstream genes. Nrf2 was repressed in transformed MSC and in breast cancer cells via oncogene-induced activation of the RAS-RAF-ERK pathway. Furthermore, restoration of Nrf2 function in transformed cells decreased reactive oxygen species and impaired in vivo tumor growth P = 0.001 by mechanisms that included sensitization to apoptosis, and a decreased hypoxic-angiogenic response through HIF-1α destabilization and VEGFA repression. Microarray analyses showed down-regulation of Nrf2 in a panel of human tumors and, strikingly, low Nrf2 expression correlated with poorer survival in patients with melanoma P = 0.0341, kidney P = 0.0203 and prostate P = 0.00279 cancers.

ConclusionsOur data indicate that oncogene-induced Nrf2 repression is an adaptive response for certain cancers to acquire a pro-oxidant state that favors cell survival and in vivo tumor growth.

KeywordsAntioxidants Nrf2 oncogenes ROS survival HIF-1α AbbreviationsMSCMesenchymal stem cell

HMECHuman mammary epithelial cells

HUVECHuman umbilical vein endothelial cells

ROSReactive oxygen species

GSEAGene set enrichment analysis

AREAntioxidant response element

TCGAThe cancer genome atlas

GEOGene expression omnibus

AsAAscorbic acid

NACN-acetyl-L-cysteine

TBHQTert-butylhydroquinone

GSHReduced glutathione

KIRCKidney renal clear cell carcinoma

PRADProstate adenocarcinoma

SKCMSkin cutaneous melanoma.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-13-20 contains supplementary material, which is available to authorized users.

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Author: Juan M Funes - Stephen Henderson - Rachel Kaufman - James M Flanagan - Mathew Robson - Barbara Pedley - Salvador Moncada

Source: https://link.springer.com/







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