Nrf2-heme oxygenase-1 axis in mucoepidermoid carcinoma of the lung: Antitumoral effects associated with down-regulation of matrix metalloproteinases

Abstract : Keywords: Mucoepidermoid carcinoma, Non-small cell lung cancer, Nrf2, Nuclear factor (erythroid-derived 2)-like 2 Heme oxygenase-1, Matrix metalloproteinases, MMP-1 Lung mucoepidermoid carcinoma (MEC) is a very poorly characterized rare subtype of non-small-cell lung cancer (NSCLC) associated with more favorable prognoses than other forms of intrathoracic ma-lignancies. We have previously identified that heme oxygenase-1 (HO-1, encoded by HMOX1) inhibits MEC tumor growth and modulates the transcriptome of microRNAs. Here we investigate the role of a major upstream regulator of HO-1 and a master regulator of cellular antioxidant responses, transcription factor Nrf2, in MEC biology. Nrf2 overexpression in the NCI-H292 MEC cell line mimicked the phenotype of HO-1 overexpressing cells, leading to inhibition of cell proliferation and migration and down-regulation of oncogenic miR-378. HMOX1 silencing identified HO-1 as a major mediator of Nrf2 action. Nrf2-and HO-1 overexpressing cells exhibited strongly diminished expression of multiple matrix metallo-proteinases and inflammatory cytokine interleukin-1β, which was confirmed in an NCI-HO-1 xenograft model. Overexpression of HO-1 altered not only human MMP levels in tumor cells but also murine MMP levels within tumor microenvironment and metastatic niche. This could possibly contribute to decreased metastasis to the lungs and inhibitory effects of HO-1 on MEC tumor growth. Our profound tran-scriptome analysis and molecular characterization of the mucoepidermoid lung carcinoma helps to understand the specific clinical presentations of these tumors, emphasizing a unique antitumoral role of the Nrf2-HO-1 axis.
Document type :
Journal articles
Complete list of metadatas

Cited literature [38 references]  Display  Hide  Download

https://hal.archives-ouvertes.fr/hal-01657418
Contributor : Isabelle Frapart <>
Submitted on : Saturday, February 10, 2018 - 7:06:22 PM
Last modification on : Friday, May 24, 2019 - 11:36:07 AM
Long-term archiving on : Friday, May 11, 2018 - 12:34:09 PM

File

MTSG.pdf
Files produced by the author(s)

Identifiers

Collections

Citation

Magdalena Tertil, Slawomir Golda, Klaudia Skrzypek, Urszula Florczyk, Kazimierz Weglarczyk, et al.. Nrf2-heme oxygenase-1 axis in mucoepidermoid carcinoma of the lung: Antitumoral effects associated with down-regulation of matrix metalloproteinases. Free Radical Biology and Medicine, Elsevier, 2015, 89, pp.147-157. ⟨10.1016/j.freeradbiomed.2015.08.004⟩. ⟨hal-01657418⟩

Share

Metrics

Record views

180

Files downloads

103