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

Laura Moreno Leon, Marine Gautier, Richard Allan, Marius Ilié, Nicolas Nottet, Nicolas Pons, Agnes Paquet, Kévin Lebrigand, Marin Truchi, Julien Fassy, Virginie Magnone, Garrett Kinnebrew, Milan Radovich, Meyling Hua Chen Cheok, Pascal Barbry, Georges Vassaux, Charles Hugo Marquette, Gilles Ponzio, Mircea Ivan, Nicolas PottierPaul Hofman, Bernard Mari, Roger Rezzonico

Research output: Contribution to journalArticle

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, 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.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Jan 1 2019

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Long Noncoding RNA
Oxidative Stress
Phenotype
Cisplatin
Clustered Regularly Interspaced Short Palindromic Repeats
Gene Knockdown Techniques
Neoplasms
Gene Expression Profiling
Caspases
Cause of Death
Exons
Lung Neoplasms
Transcription Factors
Antioxidants
Apoptosis
Biopsy
Gene Expression
Recurrence
Cell Line
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

The nuclear hypoxia-regulated NLUCAT1 long non-coding RNA contributes to an aggressive phenotype in lung adenocarcinoma through regulation of oxidative stress. / Moreno Leon, Laura; Gautier, Marine; Allan, Richard; Ilié, Marius; Nottet, Nicolas; Pons, Nicolas; Paquet, Agnes; Lebrigand, Kévin; Truchi, Marin; Fassy, Julien; Magnone, Virginie; Kinnebrew, Garrett; Radovich, Milan; Cheok, Meyling Hua Chen; Barbry, Pascal; Vassaux, Georges; Marquette, Charles Hugo; Ponzio, Gilles; Ivan, Mircea; Pottier, Nicolas; Hofman, Paul; Mari, Bernard; Rezzonico, Roger.

In: Oncogene, 01.01.2019.

Research output: Contribution to journalArticle

Moreno Leon, L, Gautier, M, Allan, R, Ilié, M, Nottet, N, Pons, N, Paquet, A, Lebrigand, K, Truchi, M, Fassy, J, Magnone, V, Kinnebrew, G, Radovich, M, Cheok, MHC, Barbry, P, Vassaux, G, Marquette, CH, Ponzio, G, Ivan, M, Pottier, N, Hofman, P, Mari, B & Rezzonico, R 2019, 'The nuclear hypoxia-regulated NLUCAT1 long non-coding RNA contributes to an aggressive phenotype in lung adenocarcinoma through regulation of oxidative stress', Oncogene. https://doi.org/10.1038/s41388-019-0935-y
Moreno Leon, Laura ; Gautier, Marine ; Allan, Richard ; Ilié, Marius ; Nottet, Nicolas ; Pons, Nicolas ; Paquet, Agnes ; Lebrigand, Kévin ; Truchi, Marin ; Fassy, Julien ; Magnone, Virginie ; Kinnebrew, Garrett ; Radovich, Milan ; Cheok, Meyling Hua Chen ; Barbry, Pascal ; Vassaux, Georges ; Marquette, Charles Hugo ; Ponzio, Gilles ; Ivan, Mircea ; Pottier, Nicolas ; Hofman, Paul ; Mari, Bernard ; Rezzonico, Roger. / The nuclear hypoxia-regulated NLUCAT1 long non-coding RNA contributes to an aggressive phenotype in lung adenocarcinoma through regulation of oxidative stress. In: Oncogene. 2019.
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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, 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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T1 - The nuclear hypoxia-regulated NLUCAT1 long non-coding RNA contributes to an aggressive phenotype in lung adenocarcinoma through regulation of oxidative stress

AU - Moreno Leon, Laura

AU - Gautier, Marine

AU - Allan, Richard

AU - Ilié, Marius

AU - Nottet, Nicolas

AU - Pons, Nicolas

AU - Paquet, Agnes

AU - Lebrigand, Kévin

AU - Truchi, Marin

AU - Fassy, Julien

AU - Magnone, Virginie

AU - Kinnebrew, Garrett

AU - Radovich, Milan

AU - Cheok, Meyling Hua Chen

AU - Barbry, Pascal

AU - Vassaux, Georges

AU - Marquette, Charles Hugo

AU - Ponzio, Gilles

AU - Ivan, Mircea

AU - Pottier, Nicolas

AU - Hofman, Paul

AU - Mari, Bernard

AU - Rezzonico, Roger

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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, 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.

AB - 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, 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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