Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation
| Autor: | Avani A. Deshpande, Ivan Barannikov, Philip R. Quinlan, Marco Napoli, Jurgen Mitsch, Cristian Coarfa, Isabelle Bedrosian, Elsa R. Flores, Xiaobo Li, Kimal Rajapakshe, Preethi H. Gunaratne, Marlese A. Pisegna, Anthony M. Magliocco, Kenneth Y. Tsai, Alastair M. Thompson, Douglas C. Marchion, Hayley D. Ackerman |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
General Physics and Astronomy Metastasis Mice 0302 clinical medicine RNA-Seq lcsh:Science Regulation of gene expression Multidisciplinary Effector Nuclear Proteins Signal transducing adaptor protein Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis Disease Progression Experimental pathology Female RNA Long Noncoding Signal Transduction Science Primary Cell Culture Breast Neoplasms Adenocarcinoma Biology Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Mammary Glands Animal Cell Line Tumor medicine Animals Humans Metastasis suppressor Protein kinase B PI3K/AKT/mTOR pathway Adaptor Proteins Signal Transducing Tumor Suppressor Proteins Mammary Neoplasms Experimental Cancer General Chemistry Phosphoproteins medicine.disease Xenograft Model Antitumor Assays 030104 developmental biology Tissue Array Analysis Trans-Activators Long non-coding RNAs Cancer research lcsh:Q Tumor Suppressor Protein p53 Proto-Oncogene Proteins c-akt Transcription Factors |
| Zdroj: | Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020) |
| ISSN: | 2041-1723 |
| Popis: | The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression. Mutations in TP53 lead to the inhibition of the tumour and metastasis suppressor TAp63, a p53 family member. By performing a mouse-human cross species analysis between the TAp63 metastatic mammary adenocarcinoma mouse model and models of human breast cancer progression, we identified two TAp63-regulated oncogenic lncRNAs, TROLL-2 and TROLL-3. Further, using a pan-cancer analysis of human cancers and multiple mouse models of tumour progression, we revealed that these two lncRNAs induce the activation of AKT to promote cancer progression by regulating the nuclear to cytoplasmic translocation of their effector, WDR26, via the shuttling protein NOLC1. Our data provide preclinical rationale for the implementation of these lncRNAs and WDR26 as therapeutic targets for the treatment of human tumours dependent upon mutant TP53 and/or the PI3K/AKT pathway. Mutations in TP53 and hyperactivation of the PI3K/AKT pathway are the two most frequent drivers of cancer progression across multiple human tumour types. Here, the authors identify two TAp63 regulated long non-coding RNAs, TROLL-2 and TROLL-3, that connect these oncogenic pathways, thus promoting tumour and metastasis formation in a wide variety of cancer types. |
| Databáze: | OpenAIRE |
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