In:
JNCI: Journal of the National Cancer Institute, Oxford University Press (OUP), Vol. 112, No. 4 ( 2020-04-01), p. 356-368
Abstract:
Tumor growth can be addicted to vital oncogenes, but whether long noncoding RNAs (lncRNAs) are essential to cancer survival is largely uncharacterized. Methods We retrieved Gene Expression Omnibus datasets to identify lncRNA overexpression in 257 cancers vs 196 normal tissues and analyzed the association of ST8SIA6-AS1 (termed Aurora A/Polo-like-kinase 1 [PLK1]–associated lncRNA, APAL) with the clinical outcomes of multiple types of cancer from public RNA sequencing 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 immunoprecipitation 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 locked nucleic acids = 0.07 g [SD = 0.02] , P & lt; .001, n = 8 mice per group; A549 xenografts: mean tumor weight control = 0.36 g [SD = 0.10] vs APAL locked nucleic acids = 0.10 g [SD = 0.04] , P & lt; .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 lncRNA in cancer cell survival and the potential of APAL as an attractive therapeutic target for a broad-spectrum of cancers.
Type of Medium:
Online Resource
ISSN:
0027-8874
,
1460-2105
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2020
detail.hit.zdb_id:
2992-0
detail.hit.zdb_id:
1465951-7
