The Role of APAL/ST8SIA6-AS1 lncRNA in PLK1 Activation and Mitotic Catastrophe of Tumor Cells
Menée à l'aide d'organoïdes et de xénogreffes sur des modèles murins, cette étude met en évidence le rôle d'un long ARN non codant dans l'activation de la kinase PLK1 et la survie des cellules cancéreuses
Background : Tumor growth can be addicted to vital oncogenes, but whether long non-coding RNAs (lncRNAs) are essential to cancer survival is largely uncharacterized.
Methods : We retrieved GEO datasets to identify lncRNAs overexpression in 257 cancers versus 196 normal tissues and analyzed the association of ST8SIA6-AS1 (termed Aurora A/PLK1 associated lncRNA, APAL) with the clinical outcomes of multiple types of cancer from the public RNA-seq and microarray datasets, as well as from in-house cancer cohorts. Loss- and gain-of-function experiments were performed to explore the role of APAL in cancers in vitro and in vivo. RNA pulldown and RNA IP were used to investigate APAL-interacting proteins. All statistical tests were two-sided.
Results : APAL is overexpressed in multiple human cancers, associated with poor clinical outcome of patients. APAL knockdown causes mitotic catastrophe and massive apoptosis in human breast, lung and pancreatic cancer cells. Overexpressing APAL accelerates cancer cell cycle progression, promotes proliferation and inhibits chemotherapy-induced apoptosis. Mechanism studies show that APAL links up PLK1 and Aurora A to enhance Aurora A-mediated PLK1 phosphorylation. Notably, targeting APAL inhibits the growth of breast and lung cancer xenografts in vivo (MCF-7 xenografts: mean tumor weight, control =0.18 g [SD = 0.03] vs APAL LNA = 0.07 g [SD = 0.02], P < 0.001, n = 8 mice per group; A549 xenografts: mean tumor weight control = 0.36 g [SD = 0.10] vs APAL LNA = 0.10 g [SD = 0.04], P < 0.001, n = 9 mice per group) and the survival of patient-derived breast cancer organoids in three-dimensional cultures.
Conclusions : Our data highlight the essential role of a lncRNA in cancer cell survival and the potential of APAL as an attractive therapeutic target for a broad-spectrum of cancers.
Journal of the National Cancer Institute , résumé, 2018