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

胃癌是全球癌症相关死亡的第二大常见原因，仅在澳大利亚每年就有数千人死于胃癌。我们已经发现了gp130受体分子基因中的一种特殊突变，这种突变导致了小鼠胃癌的形成。引人注目的是，携带这种突变的小鼠也极易患上感染性休克和腹膜炎这两种由细菌感染引起的慢性炎症性疾病的临床相关实验模型。我们现在的目标是了解这种突变导致胃壁上皮细胞不受控制生长的确切分子事件，以及导致局部和全身炎症的免疫系统不受控制的调节。在分子水平上，gp130的突变导致两个信号分子Stat1和Stat3的过度激活，这两个信号分子也被一系列其他受体用来传递特定的细胞反应。在癌症和炎症的背景下，Stat1和Stat3具有相反的作用（即Stat3促进癌症并且可以抗促炎，而Stat1抑制癌症并且促炎），尽管迄今为止，gp130受体在这些疾病中指导Stat1和Stat3激活的作用尚不清楚。我们的建议采用既定的策略和独特的小鼠模型来专门研究gp130的突变如何协调这两种分子的相反生物学功能，从而驱动胃癌和炎症。这两种分子的gp130依赖性激活与炎症和胃癌因果关系的机制鉴定将最终为靶向这些分子筛查和治疗各种炎症性疾病和癌症（包括胃癌）提供新的和合理的方法。

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.