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The nuclear hypoxia-regulated NLUCAT1 long non-coding RNA contributes to an aggressive phenotype in lung adenocarcinoma through regulation of oxidative stress

Oncogene volume 38, pages 7146–7165 (2019)Cite this article

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A Correction to this article was published on 08 March 2021

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Abstract

Lung cancer is the leading cause of cancer death worldwide, with poor prognosis and a high rate of recurrence despite early surgical removal. Hypoxic regions within tumors represent sources of aggressiveness and resistance to therapy. Although long non-coding RNAs (lncRNAs) are increasingly recognized as major gene expression regulators, their regulation and function following hypoxic stress are still largely unexplored. Combining profiling studies on early-stage lung adenocarcinoma (LUAD) biopsies and on A549 LUAD cell lines cultured in normoxic or hypoxic conditions, we identified a subset of lncRNAs that are both correlated with the hypoxic status of tumors and regulated by hypoxia in vitro. We focused on a new transcript, Nuclear LUCAT1 (NLUCAT1), which is strongly upregulated by hypoxia in vitro and correlated with hypoxic markers and poor prognosis in LUADs. Full molecular characterization showed that NLUCAT1 is a large nuclear transcript composed of six exons and mainly regulated by NF-κB and NRF2 transcription factors. CRISPR-Cas9-mediated invalidation of NLUCAT1 revealed a decrease in proliferative and invasive properties, an increase in oxidative stress and a higher sensitivity to cisplatin-induced apoptosis. Transcriptome analysis of NLUCAT1-deficient cells showed repressed genes within the antioxidant and/or cisplatin-response networks. We demonstrated that the concomitant knockdown of four of these genes products, GPX2, GLRX, ALDH3A1, and PDK4, significantly increased ROS-dependent caspase activation, thus partially mimicking the consequences of NLUCAT1 inactivation in LUAD cells. Overall, we demonstrate that NLUCAT1 contributes to an aggressive phenotype in early-stage hypoxic tumors, suggesting it may represent a new potential therapeutic target in LUADs.

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Data availability

The experimental data from microarray and RNA sequencing have been deposited in the NCBI Gene Expression Omnibus (GEO) database under SuperSerie GSE117049 containing 5 distinct datasets.

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Acknowledgements

We gratefully acknowledge the outstanding technical support of the UCA GenomiX platform and MICA imaging facility of the University Côte d’Azur, and the staff from the CHU Nice Biobank. This work was supported by Plan Cancer 2018 « ARN non-codants en cancérologie: du fondamental au translationnel » (number 18CN045), Cancéropole PACA, Fondation ARC pour la Recherche sur le Cancer, Fondation Unice (AIR project), Ligue contre le cancer (comité départemental du Nord), and the French Government (Agence Nationale de Recherche, ANR) through the Investments for the Future LABEX SIGNALIFE (ANR-11-LABX-0028-01) and FRANCE GENOMIQUE (ANR-10-INBS-09-03 and ANR-10-INBS-09-02). LML was a recipient of the Fondation pour la Recherche Médicale.

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Author notes

  1. These authors contributed equally: L. Moreno-Leon, M. Gautier

  2. These authors contributed equally: B. Mari, R. Rezzonico

Authors and Affiliations

  1. Université Côte d’Azur, CNRS UMR7275, IPMC, Valbonne, France

    Laura Moreno Leon, Marine Gautier, Richard Allan, Nicolas Nottet, Nicolas Pons, Agnes Paquet, Kévin Lebrigand, Marin Truchi, Julien Fassy, Virginie Magnone, Pascal Barbry, Gilles Ponzio & Bernard Mari

  2. FHU-OncoAge, Nice, France

    Laura Moreno Leon, Marine Gautier, Richard Allan, Marius Ilié, Nicolas Nottet, Nicolas Pons, Agnes Paquet, Kévin Lebrigand, Marin Truchi, Julien Fassy, Virginie Magnone, Pascal Barbry, Georges Vassaux, Charles-Hugo Marquette, Gilles Ponzio, Paul Hofman, Bernard Mari & Roger Rezzonico

  3. Université Côte d’Azur, CNRS, INSERM, IRCAN, Nice, France

    Marius Ilié, Charles-Hugo Marquette & Paul Hofman

  4. Hospital-Related Biobank (BB-0033-00025), Pasteur Hospital, Nice, France

    Marius Ilié & Paul Hofman

  5. Department of Surgery, Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Garrett Kinnebrew & Milan Radovich

  6. INSERM UMR-S1172, Institute for Cancer Research of Lille, Factors of Leukemia Cell Persistence, Lille, Cedex, France

    Meyling Hua-Chen Cheok

  7. Université Côte d’Azur, INSERM, CNRS UMR7275, IPMC, Valbonne, France

    Georges Vassaux & Roger Rezzonico

  8. Department of Pneumology, CHU-Nice, Nice, France

    Charles-Hugo Marquette

  9. Department of Medicine and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Mircea Ivan

  10. EA4483, Faculté de Médecine de Lille, Pole Recherche, Lille, France

    Nicolas Pottier

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  1. Laura Moreno Leon
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Correspondence to Bernard Mari or Roger Rezzonico.

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The original online version of this article was revised: The term “LUCAT1” was missing in the abstract.

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Moreno Leon, L., Gautier, M., Allan, R. et al. The nuclear hypoxia-regulated NLUCAT1 long non-coding RNA contributes to an aggressive phenotype in lung adenocarcinoma through regulation of oxidative stress. Oncogene 38, 7146–7165 (2019). https://doi.org/10.1038/s41388-019-0935-y

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