The nuclear hypoxia-regulated NLUCAT1 long non-coding RNA contributes to an aggressive phenotype in lung adenocarcinoma through regulation of oxidative stress.
Oncogene, 2019/11;38(46):7146-7165.
Moreno Leon L[1, 2], Gautier M[1, 2], Allan R[1, 2], Ilié M[2, 3, 4], Nottet N[1, 2], Pons N[1, 2], Paquet A[1, 2], Lebrigand K[1, 2], Truchi M[1, 2], Fassy J[1, 2], Magnone V[1, 2], Kinnebrew G[5], Radovich M[5], Cheok MH[6], Barbry P[1, 2], Vassaux G[2, 7], Marquette CH[2, 3, 8], Ponzio G[1, 2], Ivan M[9], Pottier N[10], Hofman P[2, 3, 4], Mari B[11, 12], Rezzonico R[13, 14]
Affiliations
PMID: 31417181DOI: 10.1038/s41388-019-0935-y
Impact factor: 8.756
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.
MeSH terms
Adenocarcinoma of Lung; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Oxidative Stress; Phenotype; RNA, Long Noncoding
More resources
EndNote: Download