Jak-Stat Signaling Induced by Interleukin-6 Family Cytokines in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. It can be caused by chronic liver cell injury with resulting sustained inflammation, e.g., triggered by infections with hepatitis viruses B (HBV) and C (HCV). Death of hepatocytes leads to the activation of compensatory mechanisms, which can ultimately result in liver fibrosis and cirrhosis. Another common feature is the infiltration of the liver with inflammatory cells, which secrete cytokines and chemokines that act directly on the hepatocytes. Among several secreted proteins, members of the interleukin-6 (IL-6) family of cytokines have emerged as important regulatory proteins that might constitute an attractive target for therapeutic intervention. The IL-6-type cytokines activate multiple intracellular signaling pathways, and especially the Jak/STAT cascade has been shown to be crucial for HCC development. In this review, we give an overview about HCC pathogenesis with respect to IL-6-type cytokines and the Jak/STAT pathway. We highlight the role of mutations in genes encoding several proteins involved in the cytokine/Jak/STAT axis and summarize current knowledge about IL-6 family cytokines in this context. We further discuss possible anti-cytokine therapies for HCC patients in comparison to already established therapies.

JAK-STAT Signalling Pathway in Cancer

“…The hallmark example is upregulated interleukin (IL)-6, which signals through either a ‘classic’ mechanism that is restricted by cell-type specific expression of IL-6 receptor α (IL-6Rα), which engages with the ubiquitously expressed β-subunit receptor, GP130. The result is increased Janus kinase (JAK) mediated activation of an oncogenic transcription factor, signal transducer and activator of transcription (STAT)3 [ 1 ]. Alternatively, IL-6 ‘trans-signalling’, mediated by IL-6 engagement with a soluble IL-6Rα, can lead to activation of JAK-STAT signalling in any cell [ 2 ].…”

“…Alternatively, IL-6 ‘trans-signalling’, mediated by IL-6 engagement with a soluble IL-6Rα, can lead to activation of JAK-STAT signalling in any cell [ 2 ]. It is now understood that a disintegrin and metalloproteinase 17 (ADAM17) is responsible for the protease-driven shedding of IL-6R [ 2 ], revealing a previously unappreciated opportunity to therapeutically modulate IL-6 mediated signalling, with extensive reviews focused on the relevance of IL-6/IL-6R/GP130 to hepatocellular carcinoma and lung cancer provided in this issue [ 1 , 2 ].…”

Circulating Neutrophils Predict Poor Survival for HCC and Promote HCC Progression Through p53 and STAT3 Signaling Pathway

“…STAT3 is phosphorylated in 60% of human HCC and active STAT3 correlates with tumor aggressiveness [13]. The Jak/STAT signaling cascade is a central signaling hub that can be activated by a plethora of cytokines, growth factors and hormones, one important of them is the interleukin-6 (IL-6) family of cytokines [14,15]. We supposed that circulating neutrophils active STAT3 signaling pathway by priming IL-6 but further researches were needed.…”

Icaritin‐induced immunomodulatory efficacy in advanced hepatitis B virus‐related hepatocellular carcinoma: Immunodynamic biomarkers and overall survival

“…Cytokines associated with the IL‐6/JAK/Stat3 pathways, 11,18,19 cross‐talk between immune cells 12,16 and immune checkpoints 20 could offer alternative immunomodulatory approaches to treat HBV‐related HCC patients. Antiinflammatory agents such as flavonoids have an array of immunomodulatory anticancer activities that include immune modulation of the balance between T helper type I (Th1) and type II (Th2) cells 10,21 .…”