Cargando…

Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer

The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage resp...

Descripción completa

Detalles Bibliográficos
Autores principales: Read, Martin L., Fong, Jim C.W., Modasia, Bhavika, Fletcher, Alice, Imruetaicharoenchoke, Waraporn, Thompson, Rebecca, Nieto, Hannah, Reynolds, John J., Bacon, Andrea, Mallick, Ujjal, Hackshaw, Allan, Watkinson, John C., Boelaert, Kristien, Turnell, Andrew S., Smith, Vicki E., McCabe, Christopher J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563453/
https://www.ncbi.nlm.nih.gov/pubmed/28504713
http://dx.doi.org/10.1038/onc.2017.154
_version_ 1783258138891255808
author Read, Martin L.
Fong, Jim C.W.
Modasia, Bhavika
Fletcher, Alice
Imruetaicharoenchoke, Waraporn
Thompson, Rebecca
Nieto, Hannah
Reynolds, John J.
Bacon, Andrea
Mallick, Ujjal
Hackshaw, Allan
Watkinson, John C.
Boelaert, Kristien
Turnell, Andrew S.
Smith, Vicki E.
McCabe, Christopher J.
author_facet Read, Martin L.
Fong, Jim C.W.
Modasia, Bhavika
Fletcher, Alice
Imruetaicharoenchoke, Waraporn
Thompson, Rebecca
Nieto, Hannah
Reynolds, John J.
Bacon, Andrea
Mallick, Ujjal
Hackshaw, Allan
Watkinson, John C.
Boelaert, Kristien
Turnell, Andrew S.
Smith, Vicki E.
McCabe, Christopher J.
author_sort Read, Martin L.
collection PubMed
description The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF and PTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P=2.4x10(-4)) compared to either PBF- (P=1.5x10(-3)) or PTTG-expressing thyrocytes (P=NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes (mean GI index of 35.8±2.6%), as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA datasets (n=322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the RTK-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well-described to drive neoplastic growth. We also showed that overall survival (P=1.91x10(-5)) and disease-free survival (P=4.9x10(-5)) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role in promoting thyroid cancer that is predictive of poorer patient outcome.
format Online
Article
Text
id pubmed-5563453
institution National Center for Biotechnology Information
language English
publishDate 2017
record_format MEDLINE/PubMed
spelling pubmed-55634532017-11-15 Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer Read, Martin L. Fong, Jim C.W. Modasia, Bhavika Fletcher, Alice Imruetaicharoenchoke, Waraporn Thompson, Rebecca Nieto, Hannah Reynolds, John J. Bacon, Andrea Mallick, Ujjal Hackshaw, Allan Watkinson, John C. Boelaert, Kristien Turnell, Andrew S. Smith, Vicki E. McCabe, Christopher J. Oncogene Article The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF and PTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P=2.4x10(-4)) compared to either PBF- (P=1.5x10(-3)) or PTTG-expressing thyrocytes (P=NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes (mean GI index of 35.8±2.6%), as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA datasets (n=322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the RTK-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well-described to drive neoplastic growth. We also showed that overall survival (P=1.91x10(-5)) and disease-free survival (P=4.9x10(-5)) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role in promoting thyroid cancer that is predictive of poorer patient outcome. 2017-05-15 2017-09-14 /pmc/articles/PMC5563453/ /pubmed/28504713 http://dx.doi.org/10.1038/onc.2017.154 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Read, Martin L.
Fong, Jim C.W.
Modasia, Bhavika
Fletcher, Alice
Imruetaicharoenchoke, Waraporn
Thompson, Rebecca
Nieto, Hannah
Reynolds, John J.
Bacon, Andrea
Mallick, Ujjal
Hackshaw, Allan
Watkinson, John C.
Boelaert, Kristien
Turnell, Andrew S.
Smith, Vicki E.
McCabe, Christopher J.
Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer
title Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer
title_full Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer
title_fullStr Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer
title_full_unstemmed Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer
title_short Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer
title_sort elevated pttg and pbf predicts poor patient outcome and modulates dna damage response genes in thyroid cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563453/
https://www.ncbi.nlm.nih.gov/pubmed/28504713
http://dx.doi.org/10.1038/onc.2017.154
work_keys_str_mv AT readmartinl elevatedpttgandpbfpredictspoorpatientoutcomeandmodulatesdnadamageresponsegenesinthyroidcancer
AT fongjimcw elevatedpttgandpbfpredictspoorpatientoutcomeandmodulatesdnadamageresponsegenesinthyroidcancer
AT modasiabhavika elevatedpttgandpbfpredictspoorpatientoutcomeandmodulatesdnadamageresponsegenesinthyroidcancer
AT fletcheralice elevatedpttgandpbfpredictspoorpatientoutcomeandmodulatesdnadamageresponsegenesinthyroidcancer
AT imruetaicharoenchokewaraporn elevatedpttgandpbfpredictspoorpatientoutcomeandmodulatesdnadamageresponsegenesinthyroidcancer
AT thompsonrebecca elevatedpttgandpbfpredictspoorpatientoutcomeandmodulatesdnadamageresponsegenesinthyroidcancer
AT nietohannah elevatedpttgandpbfpredictspoorpatientoutcomeandmodulatesdnadamageresponsegenesinthyroidcancer
AT reynoldsjohnj elevatedpttgandpbfpredictspoorpatientoutcomeandmodulatesdnadamageresponsegenesinthyroidcancer
AT baconandrea elevatedpttgandpbfpredictspoorpatientoutcomeandmodulatesdnadamageresponsegenesinthyroidcancer
AT mallickujjal elevatedpttgandpbfpredictspoorpatientoutcomeandmodulatesdnadamageresponsegenesinthyroidcancer
AT hackshawallan elevatedpttgandpbfpredictspoorpatientoutcomeandmodulatesdnadamageresponsegenesinthyroidcancer
AT watkinsonjohnc elevatedpttgandpbfpredictspoorpatientoutcomeandmodulatesdnadamageresponsegenesinthyroidcancer
AT boelaertkristien elevatedpttgandpbfpredictspoorpatientoutcomeandmodulatesdnadamageresponsegenesinthyroidcancer
AT turnellandrews elevatedpttgandpbfpredictspoorpatientoutcomeandmodulatesdnadamageresponsegenesinthyroidcancer
AT smithvickie elevatedpttgandpbfpredictspoorpatientoutcomeandmodulatesdnadamageresponsegenesinthyroidcancer
AT mccabechristopherj elevatedpttgandpbfpredictspoorpatientoutcomeandmodulatesdnadamageresponsegenesinthyroidcancer