Seminar

Inflammation and Cancer: Functions of AP-1 (Fos/Jun) proteins in mice and humans

Erwin Wagner, PhD

Investigating the molecular factors determining cell proliferation, survival or death is essential for understanding the pathogenesis of diseases including liver and skin cancers and for identifying novel therapeutic approaches. In hepatitis and inflammation-associated liver cancer, but also during liver regeneration, the expression of Jun/AP-1 is critically important (1). Using genetically modified alleles, we have analyzed the Jun upstream MAP Kinases JNK and p38 as well as the p53/TNFα pathway in inflammatory liver disease and cancer (2,3). The functions of JNK1/2 and p38α were investigated during liver cancer development using a chemical carcinogenesis protocol employing DEN/Pb. Mice with liver-specific deletion of p38α show enhanced tumor development and increased proliferation of p38α-deficient hepatocytes (2), whereas tumor development was found suppressed by inactivation of JNK1 (3). These data demonstrate that while p38α MAPK suppresses liver cancer development, JNK1 plays an oncogenic role. Recent data have identified a novel Jun-Fos-dependent oncogenic transcriptional network in liver cancer stem cells through SIRT-6-mediated epigenetic regulation of Survivin. The impact on therapeutic applications as well as the expression of components of this pathway in human hepatocellular carcinomas, HCCs will be discussed. The mouse skin/epidermis has become an important model to study the regulation and function of Fos and Jun in physiological and disease processes including stem cells, inflammation and cancer. Mouse models and human data revealed the importance of Jun proteins in inflammatory skin disease, such as Psoriasis (4, 5). I will present recent mouse and human proteomic data aimed at identifying novel therapeutic targets for Psoriasis and will demonstrate a function of c-Fos in skin cancer development with the implications of inhibiting c-Fos for potential therapeutic approaches in squamous cell carcinomas, SCCs.