Hypoxia-induced activation of NDR2 underlies brain metastases from Non-Small Cell Lung Cancer - Normandie Université Accéder directement au contenu
Article Dans Une Revue Cell Death and Disease Année : 2023

Hypoxia-induced activation of NDR2 underlies brain metastases from Non-Small Cell Lung Cancer

Résumé

The molecular mechanisms induced by hypoxia are misunderstood in non-small cell lung cancer (NSCLC), and above all the hypoxia and RASSF1A/Hippo signaling relationship. We confirmed that human NSCLC (n = 45) as their brain metastases (BM) counterpart are hypoxic since positive with CAIX-antibody (target gene of Hypoxia-inducible factor (HIF)). A severe and prolonged hypoxia (0.2% O2, 48 h) activated YAP (but not TAZ) in Human Bronchial Epithelial Cells (HBEC) lines by downregulating RASSF1A/kinases Hippo (except for NDR2) regardless their promoter methylation status. Subsequently, the NDR2-overactived HBEC cells exacerbated a HIF-1A, YAP and C-Jun-dependent-amoeboid migration, and mainly, support BM formation. Indeed, NDR2 is more expressed in human tumor of metastatic NSCLC than in human localized NSCLC while NDR2 silencing in HBEC lines (by shRNA) prevented the xenograft formation and growth in a lung cancer-derived BM model in mice. Collectively, our results indicated that NDR2 kinase is over-active in NSCLC by hypoxia and supports BM formation. NDR2 expression is thus a useful biomarker to predict the metastases risk in patients with NSCLC, easily measurable routinely by immunohistochemistry on tumor specimens.
Fichier principal
Vignette du fichier
2023_LevalletJ_CellDeathDisease.pdf (4.92 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte
Licence : CC BY - Paternité

Dates et versions

hal-04404933 , version 1 (19-01-2024)

Licence

Paternité

Identifiants

Citer

Jérôme Levallet, Tiphaine Biojout, Céline Bazille, Manon Douyère, Fatéméh Dubois, et al.. Hypoxia-induced activation of NDR2 underlies brain metastases from Non-Small Cell Lung Cancer. Cell Death and Disease, 2023, 14, pp.823. ⟨10.1038/s41419-023-06345-3⟩. ⟨hal-04404933⟩
10 Consultations
1 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More