Man-Li Luo1,2, Jingjing Li1,3, Liping Shen1,3, Junjun Chu1,3, Qiannan Guo1,3, Guorun Liang1,2, Wei Wu1,3, Jianing Chen1,3, Rufu Chen1,4, Erwei Song1,3,5,6. 1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, China. 2. Medical Research Center, Guangzhou, China. 3. Breast Tumor Center, Guangzhou, China. 4. Department of Pancreatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. 5. Guangzhou Regenerative Medicine and Health Guangdong Laboratory No. 6, Guangzhou International Bio Island, Guangzhou, China. 6. Fountain-Valley Institute for Life Sciences, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Abstract
BACKGROUND: 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 < .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 < .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.
BACKGROUND: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 humancancers 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 < .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 < .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.
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