NF-κB and STAT3 - key players in liver inflammation and cancer

Abstract

Hepatocellular carcinoma (HCC), the major form of primary liver cancer, is one of the most deadly human cancers. The pathogenesis of HCC is frequently linked with continuous hepatocyte death, inflammatory cell infiltration and compensatory liver regeneration. Understanding the molecular signaling pathways driving or mediating these processes during liver tumorigenesis is important for the identification of novel therapeutic targets for this dreadful disease. The classical IKKβ-dependent NF-κB signaling pathway has been shown to promote hepatocyte survival in both developing and adult livers. In addition, it also plays a crucial role in liver inflammatory responses by controlling the expression of an array of growth factors and cytokines. One of these cytokines is IL-6, which is best known for its role in the liver acute phase response. IL-6 exerts many of its functions via activation of STAT3, a transcription factor found to be important for HCC development. This review will focus on recent studies on the roles of NF-κB and STAT3 in liver cancer. Interactions between the two pathways and their potential as therapeutic targets will also be discussed.

Figure 1

Roles of NF-κB signaling in hepatocarcinogenesis. In the injury-promoted DEN hepatocarcinogenesis model, Kupffer cells are activated by IL-1α released from dying hepatocytes. Hepatocyte NF-κB (and p38α) inhibits this process by promoting hepatocyte survival. In low-grade, chronic, inflammation-promoted HCC models, hepatocytes with activated NF-κB produce cytokines and chemokines which activate Kupffer cells and recruit and activate other inflammatory cells and thereby maintain an inflammatory microenvironment. In both models, activated Kupffer cells produce cytokines and growth factors, such as IL-6, that are essential for the expansion of mutated hepatocytes and subsequent HCC development. Production of such cytokines by Kupffer cells is NF-κB dependent.