Coordination of hepatic and myeloid signal transducer and activator of transcription 3 in governing liver carcinogenesis and regeneration (100.36)

Abstract

Abstract Activation of signal transducer and activator of transcription 3 (STAT3) occurs virtually in most liver diseases, but how STAT3 links liver regeneration and cancer remains elusive. Using cell-specific STAT3 deletions mouse strains, we have investigated the interplay of myeloid and hepatic STAT3 in controlling liver regeneration induced by partial hepatectomy (PHx) and hepatocarcinogenesis induced by diethylinitrosamine (DEN). We show that in DEN model hepatic STAT3 plays an important role in mediating a cytoprotective action and enhancing tumor growth, while myeloid STAT3 also significantly affects tumor growth via its anti-inflammatory effect. Furthermore, STAT3 is activated in myeloid cells after PHx and its conditional deletion leads to enhanced innate inflammatory response and liver regeneration. Conditional deletion of STAT3 in both hepatocytes and myeloid cells results in strong elevated inflammatory response, activation of STAT1, apoptosis of hepatocytes and a dramatic reduction in survival after PHx, whereas additional global deletion of STAT1 protects against these effects. These data show that the interplay of myeloid and hepatic STAT3 signaling is essential to prevent acute liver failure during liver regeneration through tempering a strong innate inflammatory response mediated by STAT1 signaling. Secondly, orchestral crosstalk between hepatic and myeloid STAT3 enables survival of mutagenized cells and subsequent tumor promotion in DEN-induced hepatocarcinogenesis.