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 and Jenkins, John R (2016) Secreted HMGB1 from Wnt activated intestinal cells is required to maintain a crypt progenitor phenotype. ONCOTARGET, 7 (32). pp. 51665-51673.

Access the full-text of this item by clicking on the Open Access link.

Official URL: http://dx.doi.org/10.18632/oncotarget.10076

Abstract

<h4>Background and aims</h4>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 (Apcfloxmice) 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.<h4>Results</h4>Elevated HMGB1 was confirmed in intestinal epithelia and serum following conditional loss of Apc. Treatment of Apcflox 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.<h4>Methods</h4>Hmgb1 levels in intestinal epithelia and serum in Apcflox and ApcMin 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 Apcflox mice.<h4>Conclusions</h4>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.

Item Type:	Article
Uncontrolled Keywords:	Hmgb1, colorectal cancer, intestinal stem cells, Apc, Wnt signalling
Depositing User:	Symplectic Admin
Date Deposited:	01 Feb 2019 16:17
Last Modified:	19 Jan 2023 01:05
DOI:	10.18632/oncotarget.10076
Open Access URL:	https://doi.org/10.18632/oncotarget.10076
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3032140