Oncotarget

Research Papers:

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

Karen R. Reed _, Fei Song, Maddy A. Young, Nurudeen Hassan, Daniel J. Antoine, Nesibe-Princess B. Gemici, Alan R. Clarke and John R. Jenkins

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:51665-51673. https://doi.org/10.18632/oncotarget.10076

Metrics: PDF 2629 views  |   HTML 2554 views  |   ?  


Abstract

Karen R. Reed1, Fei Song2,3, Maddy A. Young1, Nurudeen Hassan1,4, Daniel J. Antoine3, Nesibe-Princess B. Gemici1, Alan R. Clarke1, John R. Jenkins3

1European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, CF24 4HQ, UK

2Infrafrontier GmbH, Neuherberg / München, 85764, Germany

3Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, UK

4Cardiff School of Health Sciences at Cardiff Metropolitan University, Cardiff, CF5 2YB, UK

Correspondence to:

Karen R. Reed, email: [email protected]

Keywords: Hmgb1, colorectal cancer, intestinal stem cells, Apc, Wnt signalling

Received: March 22, 2016     Accepted: May 29, 2016     Published: June 15, 2016

ABSTRACT

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 (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.

Results: 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.

Methods: 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.

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 10076