Inflammation- and stress-related signaling pathways in hepatocarcinogenesis

Abstract

It has been established that cancer can be promoted and exacerbated by inflammation. Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and its long-term prognosis remains poor. Although HCC is a complex and heterogeneous tumor with several genomic mutations, it usually develops in the context of chronic liver damage and inflammation, suggesting that understanding the mechanism(s) of inflammation-mediated hepatocarcinogenesis is essential for the treatment and prevention of HCC. Chronic liver damage induces a persistent cycle of necro-inflammation and hepatocyte regeneration, resulting in genetic mutations in hepatocytes and expansion of initiated cells, eventually leading to HCC development. Recently, several inflammation- and stress-related signaling pathways have been identified as key players in these processes, which include the nuclear factor-κB, signal transducer and activator of transcription, and stress-activated mitogen- activated protein kinase pathways. Although these pathways may suggest potential therapeutic targets, they have a wide range of functions and complex crosstalk occurs among them. This review focuses on recent advances in our understanding of the roles of these signaling pathways in hepatocarcinogenesis.

Keywords: Apoptosis signal-regulating kinase 1; Hepatocellular carcinoma; Inflammation; Mitogen-activated protein kinase; Nuclear factor-κB; Signal transducer and activator of transcription; Transforming growth factor-activated kinase 1; c-Jun NH2-terminal kinase; p38.

Figure 1

Role of inflammation- and stress-related signaling pathways in hepatocarcinogenesis. Chronic liver damage induces a persistent cycle of necro-inflammation and hepatocyte regeneration, resulting in genetic mutations in hepatocytes and expansion of initiated cells, eventually leading to hepatocellular carcinoma (HCC) development. As shown in the figure, nuclear factor-κB, signal transducer and activator of transcription 3, and stress-activated mitogen-activated protein kinase pathways play critical roles in these processes. Furthermore, other factors, such as obesity and impaired expression of microRNA, can modify these inflammatory processes and accelerate HCC development. ROS: Reactive oxygen species; TLR: Toll-like receptor; NF-κB: Nuclear factor-κB; TNF: Tumor necrosis factor; IL: Interleukin; JNK: c-Jun NH₂ terminal kinase; STAT: Signal transducer and activator of transcription.

Figure 2

Implications and regulatory system of interleukin-6/gp130/janus activated kinase/signal transducer and activator of transcription 3 signaling in hepatocarcinogenesis. Interleukin (IL)-6 secreted by Kupffer cells activates signal transducer and activator of transcription (STAT) 3, which promotes the proliferation and survival of initiated hepatocytes. STAT3 activation is suppressed by I κB kinase β through the prevention of reactive oxygen species. However, once STAT3 is activated, STAT3 activation becomes sustained through a microRNA feedback inflammatory loop. JAK: Janus activated kinase; SOCS3: Suppressor of cytokine signaling 3; IKK: I κB kinase; HNF: Hepatocyte nuclear factor; ROS: Reactive oxygen species.