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.

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

“…While safety remains a point of concern, given the fact that STAT3-null mice are embryonically lethal, tissue-specific STAT3 deletion experiments have indicated that STAT3 may not be essential for the survival of normal differentiated cells. These results provide further evidence that it may be safe to target STAT3 for HCC therapy [206].…”

Signal Transducer and Activator of Transcription 3 - A Promising Target in Colitis-Associated Cancer

“…Both proteins are not only persistently activated in cancer and essential for transducing cytoplasmic signals from extracellular stimuli, but they also function as nuclear transcription factors required for regulating genes involved in tumor proliferation, survival, angiogenesis and invasion, in addition to genes encoding key cancerpromoting inflammatory mediators (Karin and Greten, 2005;Baud and Karin, 2009;Yu and Jove, 2004;Yu et al, 2007;Darnell, 2002). NF-κB and STAT3 play a critical role in many cancers including, hepatic (He and Karin, 2011), prostate (Shanmugam et al, 2011), Lung (Tyagi et al, 2009) and breast cancer (Seo et al, 2012) which was evident from the previous reports.…”

“…In tumors, STAT3 directly interacts with the NF-κB family member RelA, trapping it in the nucleus and thereby contributing to constitutive NF-κB activation in tumor (Lee et al, 2009). Ultimately, STAT3 and NF-κB also co-regulate numerous oncogenic and inflammatory genes (Darnell et al, 2002;Yu and Jove, 2004;Yu et al, 2007;Ogura et al, 2008;He and Karin, 2011). Continuous deregulation of these genes in tumor cells and the tumor microenvironment by persistently activated STAT3 and NF-κB-in contrast to their tightly controlled regulation in normal physiology is crucial for inflammation and malignant progression.…”

NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer

“…Third, many cytokines like IL-6 induced by NF-κB or STAT3 can feedback to induce STAT3 and NF-κB activation (Gao et al, 2007;Sansone et al, 2007;Grivennikov and Karin, 2008). Through their functional interaction, NF-κB and STAT3 collaboratively promote tumor development via induction of pro-tumorigenic genes including genes in angiogenesis and hypoxia, chemokines and immunosuppressive cytokines (Bollrath and Greten, 2009;Atkinson et al, 2010;He and Karin, 2011).…”