Cargando…

Secreted HMGB1 from Wnt activated intestinal cells is required to maintain a crypt progenitor phenotype

BACKGROUND AND AIMS: Colorectal cancer (CRC) arises via multiple genetic changes. Mutation of the tumour suppressor gene APC, a key regulator of Wnt signalling, is recognised as a frequent early driving mutation in CRC. We have previously shown that conditional loss of Apc within the murine small in...

Descripción completa

Detalles Bibliográficos
Autores principales: Reed, Karen R., Song, Fei, Young, Maddy A., Hassan, Nurudeen, Antoine, Daniel J., Gemici, Nesibe-Princess B., Clarke, Alan R., Jenkins, John R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239505/
https://www.ncbi.nlm.nih.gov/pubmed/27323825
http://dx.doi.org/10.18632/oncotarget.10076
_version_ 1782495908302159872
author Reed, Karen R.
Song, Fei
Young, Maddy A.
Hassan, Nurudeen
Antoine, Daniel J.
Gemici, Nesibe-Princess B.
Clarke, Alan R.
Jenkins, John R.
author_facet Reed, Karen R.
Song, Fei
Young, Maddy A.
Hassan, Nurudeen
Antoine, Daniel J.
Gemici, Nesibe-Princess B.
Clarke, Alan R.
Jenkins, John R.
author_sort Reed, Karen R.
collection PubMed
description BACKGROUND AND AIMS: Colorectal cancer (CRC) arises via multiple genetic changes. Mutation of the tumour suppressor gene APC, a key regulator of Wnt signalling, is recognised as a frequent early driving mutation in CRC. We have previously shown that conditional loss of Apc within the murine small intestine (Apc(flox)mice) results in acute Wnt signalling activation, altered crypt-villus architecture and many hallmarks of neoplasia. Our transctipomic profiling (Affymetrix Microarrays) and proteomic profiling (iTRAQ-QSTAR) of Apc-deficient intestine inferred the involvement of High Mobility Group Box 1 (Hmgb1) in CRC pathogenesis. Here we assess the contribution of HMGB1 to the crypt progenitor phenotype seen following Apc loss. RESULTS: Elevated HMGB1 was confirmed in intestinal epithelia and serum following conditional loss of Apc. Treatment of Apc(flox) mice with anti-HMGB1 neutralising antibody significantly reduced many of the crypt progenitor phenotypes associated with Apc loss; proliferation and apoptosis levels were reduced, cell differentiation was restored and the expansion of stem cell marker expression was eradicated. METHODS: Hmgb1 levels in intestinal epithelia and serum in Apc(flox) and Apc(Min) mice were assessed using qRT-PCR, Western blot and ELISA assays. The functional importance of elevated extracellular Hmgb1 was assessed using an anti-HMGB1 neutralising antibody in Apc(flox) mice. CONCLUSIONS: HMGB1 is expressed and secreted from intestinal epithelial cells in response to Wnt signalling activation. This secreted HMGB1 is required to maintain nearly all aspects of the crypt progenitor phenotype observed following Apc loss and add to the body of accumulating evidence indicating that targeting HMGB1 may be a viable novel therapeutic approach.
format Online
Article
Text
id pubmed-5239505
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-52395052017-01-24 Secreted HMGB1 from Wnt activated intestinal cells is required to maintain a crypt progenitor phenotype Reed, Karen R. Song, Fei Young, Maddy A. Hassan, Nurudeen Antoine, Daniel J. Gemici, Nesibe-Princess B. Clarke, Alan R. Jenkins, John R. Oncotarget Research Paper BACKGROUND AND AIMS: Colorectal cancer (CRC) arises via multiple genetic changes. Mutation of the tumour suppressor gene APC, a key regulator of Wnt signalling, is recognised as a frequent early driving mutation in CRC. We have previously shown that conditional loss of Apc within the murine small intestine (Apc(flox)mice) results in acute Wnt signalling activation, altered crypt-villus architecture and many hallmarks of neoplasia. Our transctipomic profiling (Affymetrix Microarrays) and proteomic profiling (iTRAQ-QSTAR) of Apc-deficient intestine inferred the involvement of High Mobility Group Box 1 (Hmgb1) in CRC pathogenesis. Here we assess the contribution of HMGB1 to the crypt progenitor phenotype seen following Apc loss. RESULTS: Elevated HMGB1 was confirmed in intestinal epithelia and serum following conditional loss of Apc. Treatment of Apc(flox) mice with anti-HMGB1 neutralising antibody significantly reduced many of the crypt progenitor phenotypes associated with Apc loss; proliferation and apoptosis levels were reduced, cell differentiation was restored and the expansion of stem cell marker expression was eradicated. METHODS: Hmgb1 levels in intestinal epithelia and serum in Apc(flox) and Apc(Min) mice were assessed using qRT-PCR, Western blot and ELISA assays. The functional importance of elevated extracellular Hmgb1 was assessed using an anti-HMGB1 neutralising antibody in Apc(flox) mice. CONCLUSIONS: HMGB1 is expressed and secreted from intestinal epithelial cells in response to Wnt signalling activation. This secreted HMGB1 is required to maintain nearly all aspects of the crypt progenitor phenotype observed following Apc loss and add to the body of accumulating evidence indicating that targeting HMGB1 may be a viable novel therapeutic approach. Impact Journals LLC 2016-06-15 /pmc/articles/PMC5239505/ /pubmed/27323825 http://dx.doi.org/10.18632/oncotarget.10076 Text en Copyright: © 2016 Reed et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Reed, Karen R.
Song, Fei
Young, Maddy A.
Hassan, Nurudeen
Antoine, Daniel J.
Gemici, Nesibe-Princess B.
Clarke, Alan R.
Jenkins, John R.
Secreted HMGB1 from Wnt activated intestinal cells is required to maintain a crypt progenitor phenotype
title Secreted HMGB1 from Wnt activated intestinal cells is required to maintain a crypt progenitor phenotype
title_full Secreted HMGB1 from Wnt activated intestinal cells is required to maintain a crypt progenitor phenotype
title_fullStr Secreted HMGB1 from Wnt activated intestinal cells is required to maintain a crypt progenitor phenotype
title_full_unstemmed Secreted HMGB1 from Wnt activated intestinal cells is required to maintain a crypt progenitor phenotype
title_short Secreted HMGB1 from Wnt activated intestinal cells is required to maintain a crypt progenitor phenotype
title_sort secreted hmgb1 from wnt activated intestinal cells is required to maintain a crypt progenitor phenotype
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239505/
https://www.ncbi.nlm.nih.gov/pubmed/27323825
http://dx.doi.org/10.18632/oncotarget.10076
work_keys_str_mv AT reedkarenr secretedhmgb1fromwntactivatedintestinalcellsisrequiredtomaintainacryptprogenitorphenotype
AT songfei secretedhmgb1fromwntactivatedintestinalcellsisrequiredtomaintainacryptprogenitorphenotype
AT youngmaddya secretedhmgb1fromwntactivatedintestinalcellsisrequiredtomaintainacryptprogenitorphenotype
AT hassannurudeen secretedhmgb1fromwntactivatedintestinalcellsisrequiredtomaintainacryptprogenitorphenotype
AT antoinedanielj secretedhmgb1fromwntactivatedintestinalcellsisrequiredtomaintainacryptprogenitorphenotype
AT gemicinesibeprincessb secretedhmgb1fromwntactivatedintestinalcellsisrequiredtomaintainacryptprogenitorphenotype
AT clarkealanr secretedhmgb1fromwntactivatedintestinalcellsisrequiredtomaintainacryptprogenitorphenotype
AT jenkinsjohnr secretedhmgb1fromwntactivatedintestinalcellsisrequiredtomaintainacryptprogenitorphenotype