Poster Presentation 31st Lorne Cancer Conference 2019

Loss of Bcl-g predisposes the development of inflammation-associated colorectal cancer (#342)

Paul M Nguyen 1 , Laura F Dagley 1 , Adele Preaudet 1 , Ka Yee Fung 1 , Chin Wee Tan 1 , Yumiko Hirokawa 1 , Lotta Burstroem 1 , Rebecca Feltham 1 , Suad Abdirahman 1 , Andrew I Webb 1 , Tony Burgess 1 , Oliver Sieber 1 , Philippe Bouillet 1 , Tracy L Putoczki 1
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

BACKGROUND: The gastrointestinal (GI) tract is lined by a single layer of epithelial cells, with defects in these cells implicated in the pathogenesis of inflammatory bowel disease and colorectal cancer (CRC). BCL-G is a member of the Bcl-2 family of proteins, consisting of a long and short isoform in humans, and one isoform in mice, and is highly expressed by GI epithelial cells. Unlike the other members of the BCL-2 family, no clear pro- or anti- apoptotic role has been attributed to this protein. We examined the role of BCL-G in CRC cancer.

METHODS: Using BCL-G deficient mice, we investigated the role of this protein in tumour development in two colorectal cancer models: the AOM/DSS model of colitis-associated cancer, and the ApcMIN model of sporadic CRC. We examined tumour burden in these mice, and performed immunohistochemistry to determine proliferation, apoptosis, and inflammation in the tumours. Additionally, a label-free quantitative proteomics analysis was performed on naïve and DSS treated mice to determine potential proteins which may be associated with BCL-G function. 

RESULTS: We demonstrate that Bcl-G is highly expressed in the epithelial cells of the GI tract of mice during development through to adulthood, and show that its absence accelerates the progression of colitis-associated but not sporadic CRC. This tumour suppressive role for BCL-G was consistent with our observation that BCL-G expression was significantly reduced in the tumours of CRC patients. Quantification of proliferative, apoptotic, and inflammatory cells did not demonstrate a difference in BCL-G deficient mice. However, quantitative proteomics analysis of naïve and DSS treated mice demonstrated decreased expression of mucus-associated proteins including CLCA1, FCGBP, and MPTX1.

SIGNIFICANCE: Our results demonstrate that BCL-G contributes to tumour development in colitis-associated cancer in mice, potentially though interaction with mucus scaffolding proteins resulting in a change to the mucus layer that normally protects the epithelial cells and helps maintain barrier integrity.