TY - JOUR
T1 - Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation
AU - Napoli, Marco
AU - Li, Xiaobo
AU - Ackerman, Hayley D.
AU - Deshpande, Avani A.
AU - Barannikov, Ivan
AU - Pisegna, Marlese A.
AU - Bedrosian, Isabelle
AU - Mitsch, Jürgen
AU - Quinlan, Philip
AU - Thompson, Alastair
AU - Rajapakshe, Kimal
AU - Coarfa, Cristian
AU - Gunaratne, Preethi H.
AU - Marchion, Douglas C.
AU - Magliocco, Anthony M.
AU - Tsai, Kenneth Y
AU - Flores, Elsa Renee
N1 - Funding Information:
We thank Joseph Johnson and his team at the Analytic Microscopy Core Facility (Moffitt Cancer Center) for the quantification of the IHC and ISH signals, Mahmoud A. Abdalah and Olya Stringfield at the Quantitative Imaging Core (Moffitt Cancer Center) for the quantification of the lung metastases, and Lancia N. Darville-Bowleg and John M. Koomen at the Proteomics and Metabolomics Core (Moffitt Cancer Center) for the LC-MS/MS analysis. E.R.F. is a National Cancer Institute Outstanding Investigator (R35CA197452), Moffitt Distinguished Scholar, and Scholar of the Leukemia and Lymphoma Society, the Rita Allen Foundation, and the V Foundation for Cancer Research. M.N. is a Scholar of the Cancer Prevention Research Institute of Texas-Translational Research in Multidisciplinary Program and was supported by a Research Training Award (RP140106) and a grant from the Cancer Prevention and Research Institute of Texas (RP150094). K.R. and C.C. have been supported in part by NIH P30 shared resource grant CA125123, CPRIT RP170005, and NIEHS P30 Center grant 1P30ES030285. We gratefully acknowledge the assistance of Jane L. Messina (Moffitt Cancer Center) in determining the suitability of melanoma TMAs generated at Moffitt Cancer Center and the assistance of Carolyn Rich (Moffitt Cancer Center) in procuring the appropriate TMA sections. This work has been supported in part by the Tissue Core (Research Histology), Analytic Microscopy Core, Image Response Assessment Team, and Proteomics Core Facilities at the H. Lee Moffitt Cancer Center & Research Institute (P30-CA076292).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-18973-w
DO - 10.1038/s41467-020-18973-w
M3 - Article
C2 - 33056990
AN - SCOPUS:85092600574
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5156
ER -