Poster Presentation 30th Lorne Cancer Conference 2018

Manipulating c-MYC expression as a therapeutic strategy for gastric cancer (#227)

Riley J Morrow 1 2 , Ashleigh Poh 1 2 , Robert O'Donoghue 1 2 , Matthias Ernst 1 2
  1. Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia
  2. La Trobe University, School of Cancer Medicine, Bundoora, VIC, Australia

Background:

c-Myc is among the most frequently over-expressed oncogenes in human cancers, including in 40% of gastric cancers. Regulating the transcription of ~15% of all genes, c-MYC has a fundamental role in cell cycle regulation, apoptosis, angiogenesis, cell growth arrest, metabolism and differentiation. c-MYC is likely to play a profound role in the initiation and maintenance of gastric carcinogenesis due to its activation by the Jak/Stat3 and other key signalling pathways. Mediated by IL-6 and IL-11 cytokines, the Jak/Stat3 signalling cascade is excessively activated during gastric tumourigenesis, while Stat3 is known to interact with c-MYC to cooperatively regulate gene transcription.

Aim:

Previous findings from our laboratory identified a significant overlap of genes regulated by c-Myc and those by regulated IL-6 and IL-11, including Stat3, in gastric tumours from the gp130F/F gastric cancer mouse model. Here, we evaluate the requirement for c-MYC during Stat3 signalling-dependent gastric tumour formation by assessing the effects of genetically ablating c-Myc specifically in the gastric epithelium of tumour bearing mice.

Methods:

c-MYC expression was analysed in normal and tumour tissue from the antrum of gp130F/F mice by quantitative RT-PCR (qRT-PCR) and Western-blot analysis. gp130F/F;Tff1CreERT2;Mycflox compound mutant mice were treated with tamoxifen and stomachs collected. Tumour weight was recorded and tissues subjected to qRT-PCR and Western-blot analysis to monitor the activation of the Jak/Stat3 signalling cascade.

Results:

Stat3-mediated gastric tumourgenesis is partially dependent on expression of c-MYC, with RNA and protein levels being significantly increased in Stat3-driven gastric tumours in gp130F/F mice. Genetic ablation of c-Myc specifically in the gastric epithelium of gp130F/F;Tff1CreERT2;Mycflox mice significantly reduced tumour weight, as well as activation of the Jak/Stat3 signalling pathway.  

Conclusion:

Collectively, our findings indicate that excessive c-MYC expression in the epithelial compartment may contribute to gastric cancer initiation and maintenance. This suggests that c-MYC may serve as a non-redundant therapeutic target for the treatment of gastric cancer.