Abstract
Hepatocellular carcinoma (HCC) is frequently associated with pathogen infection-induced chronic inflammation. Large numbers of innate immune cells are present in HCCs and can influence disease outcome. Here, we demonstrated that the tumor suppressor serine/threonine-protein kinase 4 (STK4) differentially regulates TLR3/4/9-mediated inflammatory responses in macrophages and thereby is protective against chronic inflammation-associated HCC. STK4 dampened TLR4/9-induced proinflammatory cytokine secretion but enhanced TLR3/4-triggered IFN-β production via binding to and phosphorylating IL-1 receptor-associated kinase 1 (IRAK1), leading to IRAK1 degradation. Notably, macrophage-specific Stk4 deletion resulted in chronic inflammation, liver fibrosis, and HCC in mice treated with a combination of diethylnitrosamine (DEN) and CCl4, along with either LPS or E. coli infection. STK4 expression was markedly reduced in macrophages isolated from human HCC patients and was inversely associated with the levels of IRAK1, IL-6, and phospho-p65 or phospho-STAT3. Moreover, serum STK4 levels were specifically decreased in HCC patients with high levels of IL-6. In STK4-deficient mice, treatment with an IRAK1/4 inhibitor after DEN administration reduced serum IL-6 levels and liver tumor numbers to levels similar to those observed in the control mice. Together, our results suggest that STK4 has potential as a diagnostic biomarker and therapeutic target for inflammation-induced HCC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carbon Tetrachloride / toxicity
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Carcinoma, Hepatocellular / chemistry
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Carcinoma, Hepatocellular / etiology
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Carcinoma, Hepatocellular / immunology*
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Cytokines / metabolism
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Diethylnitrosamine
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Escherichia coli Infections / complications
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Female
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HEK293 Cells
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Hepatitis, Animal / chemically induced
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Hepatitis, Animal / immunology
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Humans
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Immunity, Innate
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Interferon-beta / biosynthesis
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Interferon-beta / genetics
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Interleukin-1 Receptor-Associated Kinases / physiology
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Interleukin-6 / analysis
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides / toxicity
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Liver Neoplasms / chemistry
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Liver Neoplasms / etiology
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Liver Neoplasms / immunology*
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Liver Neoplasms, Experimental / etiology
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Liver Neoplasms, Experimental / genetics
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Liver Neoplasms, Experimental / immunology
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Liver Neoplasms, Experimental / prevention & control
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Lung / immunology
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Lung / pathology
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Macrophages / immunology
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Macrophages / metabolism
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Male
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Mice
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Neoplasm Proteins / analysis
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Phosphorylation
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases / blood
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / physiology*
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STAT3 Transcription Factor / analysis
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Signal Transduction
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Specific Pathogen-Free Organisms
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Toll-Like Receptors / immunology*
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Transcription Factor RelA / analysis
Substances
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Cytokines
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IL6 protein, human
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides
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Neoplasm Proteins
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RELA protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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Toll-Like Receptors
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Transcription Factor RelA
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Diethylnitrosamine
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Interferon-beta
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Carbon Tetrachloride
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Stk4 protein, mouse
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STK4 protein, human
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IRAK1 protein, human
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Interleukin-1 Receptor-Associated Kinases
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Irak1 protein, mouse
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Protein Serine-Threonine Kinases