The role of TAp63γ and P53 point mutations in regulating DNA repair, mutational susceptibility and invasion of bladder cancer cells

It has long been recognized that non-muscle-invasive bladder cancer (NMIBC) has a low propensity (20%) of becoming muscle-invasive (MIBC), and that MIBC carry many more p53 point mutations (p53m) than NMIBC (50% vs 10%). MIBC also has a higher mutation burden than NMIBC. These results suggest that D...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Hsiang-Tsui Wang, Hyun-Wook Lee, Mao-wen Weng, Yan Liu, William C Huang, Herbert Lepor, Xue-Ru Wu, Moon-shong Tang
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	TAp63g p53m DNA repair mutation susceptibility bladder cancer tumor invasion Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/35cdeaf8520d46078b684f45c7b6c5d6
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:35cdeaf8520d46078b684f45c7b6c5d6
record_format	dspace
spelling	oai:doaj.org-article:35cdeaf8520d46078b684f45c7b6c5d62021-11-08T14:09:25ZThe role of TAp63γ and P53 point mutations in regulating DNA repair, mutational susceptibility and invasion of bladder cancer cells10.7554/eLife.711842050-084Xe71184https://doaj.org/article/35cdeaf8520d46078b684f45c7b6c5d62021-11-01T00:00:00Zhttps://elifesciences.org/articles/71184https://doaj.org/toc/2050-084XIt has long been recognized that non-muscle-invasive bladder cancer (NMIBC) has a low propensity (20%) of becoming muscle-invasive (MIBC), and that MIBC carry many more p53 point mutations (p53m) than NMIBC (50% vs 10%). MIBC also has a higher mutation burden than NMIBC. These results suggest that DNA repair capacities, mutational susceptibility and p53m are crucial for MIBC development. We found MIBC cells are hypermutable, deficient in DNA repair and have markedly downregulated DNA repair genes, XPC, hOGG1/2 and Ref1, and the tumor suppressor, TAp63γ. In contrast, NMIBC cells are hyperactive in DNA repair and exhibit upregulated DNA repair genes and TAp63γ. A parallel exists in human tumors, as MIBC tissues have markedly lower DNA repair activity, and lower expression of DNA repair genes and TAp63γ compared to NMIBC tissues. Forced TAp63γ expression in MIBC significantly mitigates DNA repair deficiencies and reduces mutational susceptibility. Knockdown of TAp63γ in NMIBC greatly reduces DNA repair capacity and enhances mutational susceptibility. Manipulated TAp63γ expression or knockdown of p53m reduce the invasion of MIBC by 40–60%. However, the combination of p53m knockdown with forced TAp63γ expression reduce the invasion ability to nil suggesting that p53m contributes to invasion phenotype independent from TAp63γ. These results indicate that in BC, TAp63γ regulates DNA repair capacities, mutational susceptibility and invasion, and that p53m contribute to the invasion phenotype. We conclude that concurrent TAp63γ suppression and acquisition of p53m are a major cause for MIBC development.Hsiang-Tsui WangHyun-Wook LeeMao-wen WengYan LiuWilliam C HuangHerbert LeporXue-Ru WuMoon-shong TangeLife Sciences Publications LtdarticleTAp63gp53mDNA repairmutation susceptibilitybladder cancertumor invasionMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	TAp63g p53m DNA repair mutation susceptibility bladder cancer tumor invasion Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	TAp63g p53m DNA repair mutation susceptibility bladder cancer tumor invasion Medicine R Science Q Biology (General) QH301-705.5 Hsiang-Tsui Wang Hyun-Wook Lee Mao-wen Weng Yan Liu William C Huang Herbert Lepor Xue-Ru Wu Moon-shong Tang The role of TAp63γ and P53 point mutations in regulating DNA repair, mutational susceptibility and invasion of bladder cancer cells
description	It has long been recognized that non-muscle-invasive bladder cancer (NMIBC) has a low propensity (20%) of becoming muscle-invasive (MIBC), and that MIBC carry many more p53 point mutations (p53m) than NMIBC (50% vs 10%). MIBC also has a higher mutation burden than NMIBC. These results suggest that DNA repair capacities, mutational susceptibility and p53m are crucial for MIBC development. We found MIBC cells are hypermutable, deficient in DNA repair and have markedly downregulated DNA repair genes, XPC, hOGG1/2 and Ref1, and the tumor suppressor, TAp63γ. In contrast, NMIBC cells are hyperactive in DNA repair and exhibit upregulated DNA repair genes and TAp63γ. A parallel exists in human tumors, as MIBC tissues have markedly lower DNA repair activity, and lower expression of DNA repair genes and TAp63γ compared to NMIBC tissues. Forced TAp63γ expression in MIBC significantly mitigates DNA repair deficiencies and reduces mutational susceptibility. Knockdown of TAp63γ in NMIBC greatly reduces DNA repair capacity and enhances mutational susceptibility. Manipulated TAp63γ expression or knockdown of p53m reduce the invasion of MIBC by 40–60%. However, the combination of p53m knockdown with forced TAp63γ expression reduce the invasion ability to nil suggesting that p53m contributes to invasion phenotype independent from TAp63γ. These results indicate that in BC, TAp63γ regulates DNA repair capacities, mutational susceptibility and invasion, and that p53m contribute to the invasion phenotype. We conclude that concurrent TAp63γ suppression and acquisition of p53m are a major cause for MIBC development.
format	article
author	Hsiang-Tsui Wang Hyun-Wook Lee Mao-wen Weng Yan Liu William C Huang Herbert Lepor Xue-Ru Wu Moon-shong Tang
author_facet	Hsiang-Tsui Wang Hyun-Wook Lee Mao-wen Weng Yan Liu William C Huang Herbert Lepor Xue-Ru Wu Moon-shong Tang
author_sort	Hsiang-Tsui Wang
title	The role of TAp63γ and P53 point mutations in regulating DNA repair, mutational susceptibility and invasion of bladder cancer cells
title_short	The role of TAp63γ and P53 point mutations in regulating DNA repair, mutational susceptibility and invasion of bladder cancer cells
title_full	The role of TAp63γ and P53 point mutations in regulating DNA repair, mutational susceptibility and invasion of bladder cancer cells
title_fullStr	The role of TAp63γ and P53 point mutations in regulating DNA repair, mutational susceptibility and invasion of bladder cancer cells
title_full_unstemmed	The role of TAp63γ and P53 point mutations in regulating DNA repair, mutational susceptibility and invasion of bladder cancer cells
title_sort	role of tap63γ and p53 point mutations in regulating dna repair, mutational susceptibility and invasion of bladder cancer cells
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/35cdeaf8520d46078b684f45c7b6c5d6
work_keys_str_mv	AT hsiangtsuiwang theroleoftap63gandp53pointmutationsinregulatingdnarepairmutationalsusceptibilityandinvasionofbladdercancercells AT hyunwooklee theroleoftap63gandp53pointmutationsinregulatingdnarepairmutationalsusceptibilityandinvasionofbladdercancercells AT maowenweng theroleoftap63gandp53pointmutationsinregulatingdnarepairmutationalsusceptibilityandinvasionofbladdercancercells AT yanliu theroleoftap63gandp53pointmutationsinregulatingdnarepairmutationalsusceptibilityandinvasionofbladdercancercells AT williamchuang theroleoftap63gandp53pointmutationsinregulatingdnarepairmutationalsusceptibilityandinvasionofbladdercancercells AT herbertlepor theroleoftap63gandp53pointmutationsinregulatingdnarepairmutationalsusceptibilityandinvasionofbladdercancercells AT xueruwu theroleoftap63gandp53pointmutationsinregulatingdnarepairmutationalsusceptibilityandinvasionofbladdercancercells AT moonshongtang theroleoftap63gandp53pointmutationsinregulatingdnarepairmutationalsusceptibilityandinvasionofbladdercancercells AT hsiangtsuiwang roleoftap63gandp53pointmutationsinregulatingdnarepairmutationalsusceptibilityandinvasionofbladdercancercells AT hyunwooklee roleoftap63gandp53pointmutationsinregulatingdnarepairmutationalsusceptibilityandinvasionofbladdercancercells AT maowenweng roleoftap63gandp53pointmutationsinregulatingdnarepairmutationalsusceptibilityandinvasionofbladdercancercells AT yanliu roleoftap63gandp53pointmutationsinregulatingdnarepairmutationalsusceptibilityandinvasionofbladdercancercells AT williamchuang roleoftap63gandp53pointmutationsinregulatingdnarepairmutationalsusceptibilityandinvasionofbladdercancercells AT herbertlepor roleoftap63gandp53pointmutationsinregulatingdnarepairmutationalsusceptibilityandinvasionofbladdercancercells AT xueruwu roleoftap63gandp53pointmutationsinregulatingdnarepairmutationalsusceptibilityandinvasionofbladdercancercells AT moonshongtang roleoftap63gandp53pointmutationsinregulatingdnarepairmutationalsusceptibilityandinvasionofbladdercancercells
_version_	1718442223921528832

The role of TAp63γ and P53 point mutations in regulating DNA repair, mutational susceptibility and invasion of bladder cancer cells

Ejemplares similares