The Opposing Roles of STAT1 and STAT3 Signalling by IL-6 Family Cytokines in Inflammation and Tumourigenesis [ 2006 - 2008 ]

Research Grant

Researchers: Prof Brendan Jenkins (Principal investigator) ,  Prof Matthias Ernst ,  Prof Paul Hertzog

Brief description Stomach cancer is the second most common cause of cancer-related deaths worldwide, and results in the yearly death of several thousand people in Australia alone. We have discovered a specific mutation in a gene for a receptor molecule called gp130 that results in the formation of stomach cancer in mice. Strikingly, mice with this mutation are also highly susceptible to clinically-relevant experimental models of septic shock and peritonitis, two chronic inflammatory disorders induced by bacterial infection. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of epithelial cells that line the stomach wall, as well as uncontrolled regulation of the immune system leading to local and systemic inflammation. At the molecular level, the mutation in gp130 leads to over-activation of two signalling molecules, Stat1 and Stat3, which are also used by a range of other receptors to transmit specific cellular responses. In the context of cancer and inflammation, Stat1 and Stat3 have opposing roles (ie Stat3 promotes cancer and can be both anti-pro-inflammatory, while Stat1 suppresses cancer and is pro-inflammatory), although as yet, the contribution of the gp130 receptor in directing Stat1 and Stat3 activation in these disorders is not known. Our proposal employs established strategies and unique mouse models to specifically address how the mutation in gp130 can orchestrate the opposing biological functions of these two molecules to drive stomach cancer and inflammation. The identification of mechanisms by which gp130-dependent activation of these two molecules causally relate to inflammation and stomach cancer will ultimately provide novel and rational approaches to target these molecules for the screening and treatment of various inflammatory disorders and cancers, including those of the stomach.

Funding Amount $AUD 472,770.54

Funding Scheme NHMRC Project Grants

Notes Standard Project Grant