Cytokine levels contribute to the pathogenesis of minimal hepatic encephalopathy in patients with hepatocellular carcinoma via STAT3 activation

Abstract

Hepatocellular carcinoma (HCC) patients were grouped according to the degree of encephalopathy, with healthy volunteers as controls. We investigated clinical presentation, protein and mRNA expression of 14 cytokines, and activation of six STAT proteins, the downstream signaling mediators. Levels of all 14 cytokines were significantly elevated in HCC patients with clinical hepatic encephalopathy. Statistical analysis showed that levels of IL-1β, IL-6, IFNγ, IL-17α, IFNλ2 and IFNλ3 were correlated with minimal hepatic encephalopathy (MHE). Multivariate regression analysis identified serum IL-6, IFNλ3 and IL-17α as independent risk factors for MHE. Increased mRNA levels of IL-6 and IFNγ were associated with MHE. Among the STAT proteins examined, only STAT3 was elevated in MHE. Treatment with a STAT3 inhibitor protected neurons from cytokine-induced apoptosis in vitro. In conclusion, this study identified potential biomarkers for MHE in HCC. The cytokines investigated may induce neural apoptosis via STAT3 in the pathogenesis of MHE in HCC.

Bazedoxifene exhibits growth suppressive activity by targeting interleukin‐6/glycoprotein 130/signal transducer and activator of transcription 3 signaling in hepatocellular carcinoma

“…IL‐6 released from T cells can induce proliferation and differentiation of B cells, as well as stimulate antibody production. Recent studies have revealed that the expression of IL‐6 in primary liver cancer was dramatically elevated and is positively correlated with morbidity and progression . IL‐6 exerts its biological effects through binding to two subunits of signal transducing receptor GP130 and IL‐6R, resulting in dimerization of GP130 and IL‐6R and subsequently activation of the Janus kinases/STAT3 pathway.…”

“…Indeed, activated STAT3 is necessary not only for oncogenesis and tumor progression, but also for invasion of HCC in vitro and in vivo . Levels of cytokines were found to be elevated in HCC, especially IL‐6 . IL‐6 binds to IL‐6R to form a binary complex and further combines with GP130 to transduce extracellular signaling.…”

“…Therefore, blocking the interaction between IL‐6 and GP130 may inhibit the IL‐6/GP130/STAT3 signaling pathway and its biological effects . The excessive expression of IL‐6 contributes to the pathological progression in HCC through STAT3 activation, such as in hepatocarcinogenesis, self‐renewal of liver tumor‐initiating cells, minimal hepatic encephalopathy and cancer cachexia . GP130 is a co‐receptor of the IL‐6 receptor and defined as an oncogene that is involved in the progression of hepatocellular tumors .…”

Systems Challenges of Hepatic Carcinomas: A Review

“…There is an evidence about the role of cytokines in the progression of HCC. 16 In response to infections and inflammation caused by hepatitis viruses (HBV and HCV), the inflammatory cells secrete cytokines and chemokines, which contribute to the liver damage and progression of HCC. The cytokines that were shown to be involved in the hepatocarcinogenesis are IL-1 b, IL-2, IL-1b, IFN-g, TNF-a, IL-4, IL-10, IL-6, and TGFB.…”

Poly(lactic-<em>co</em>-glycolic acid)-loaded nanoparticles of betulinic acid for improved treatment of hepatic cancer: characterization, in vitro and in vivo evaluations

“…56 B generally exerts anticancer action either by triggering the mitochondrial pathway of apoptosis or by inducing cellular stress, such as cytokine withdrawal and DNA damage. [7][8][9][10][11][12][13][14][15][16][17][18] Thus, we investigated the altered levels of cytokines and caspases among different groups through ELISA and screened the effects of B and BNP treatments over the carcinogen control group.…”