IL-1β-Induced Elevation of Solute Carrier Family 7 Member 11 Promotes Hepatocellular Carcinoma Metastasis Through Up-regulating Programmed Death Ligand 1 and Colony-Stimulating Factor 1

Hepatology. 2021 Dec;74(6):3174-3193. doi: 10.1002/hep.32062. Epub 2021 Aug 27.

Abstract

Background and aims: Because of a paucity of effective treatment options, metastasis is still a major cause for HCC-associated mortality. The molecular mechanism of inflammation-induced HCC metastasis is open for study. Here, we characterized the function of solute carrier family 7 member 11 (SLC7A11) in inflammation-related HCC metastasis and probed therapy strategies for this subpopulation of patients.

Approach and results: Elevated expression of SLC7A11 was positively correlated with poor tumor differentiation, and higher tumor-nodule-metastasis stage, and indicated poor prognosis in human HCC. SLC7A11 increased HIF1α expression through reducing α-ketoglutarate (αKG) level by exporting glutamate. SLC7A11 up-regulated programmed death ligand 1 (PD-L1) and colony-stimulating factor 1 (CSF1) expression through αKG-HIF1α cascade. SLC7A11 overexpression in HCC cells promoted intratumoral tumor-associated macrophage (TAM) and myeloid-derived suppressor cell (MDSC) infiltration through the CSF1/colony-stimulating factor 1 receptor (CSF1R) axis, whereas knockdown of CSF1 attenuated SLC7A11-mediated intratumoral TAM and MDSC infiltration and HCC metastasis. Depletion of either TAMs or MDSCs decreased SLC7A11-mediated HCC metastasis. Furthermore, the combination of CSF1R inhibitor BZL945 and anti-PD-L1 antibody blocked SLC7A11-induced HCC metastasis. In addition, IL-1β up-regulated SLC7A11 expression through the interleukin-1 receptor type 1 (IL-1R1)/extracellular signal-regulated kinase/specificity protein 1 pathway. SLC7A11 knockdown impaired IL-1β-promoted HCC metastasis. Anakinra, an IL-1R1 antagonist, reversed IL-1β-promoted HCC metastasis. In human HCC tissues, SLC7A11 expression was positively associated with HIF1α, PD-L1, and CSF1 expression and intratumoral TAM and MDSC infiltration.

Conclusions: IL-1β-induced SLC7A11 overexpression up-regulated PD-L1 and CSF1 through the αKG/HIF1α axis, which promoted TAM and MDSC infiltration. Interruption of this oncogenic loop may provide a promising therapy strategy for the inhibition of SLC7A11-mediated HCC metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System y+ / genetics*
  • Amino Acid Transport System y+ / metabolism
  • Animals
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / metabolism
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / immunology*
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / therapy
  • Cell Line, Tumor / transplantation
  • Disease Models, Animal
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / immunology
  • Gene Knockdown Techniques
  • Hepatectomy
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Interleukin 1 Receptor Antagonist Protein / pharmacology
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use
  • Interleukin-1beta / metabolism*
  • Ketoglutaric Acids / metabolism
  • Liver / immunology
  • Liver / pathology
  • Liver / surgery
  • Liver Neoplasms / genetics
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / mortality
  • Liver Neoplasms / therapy
  • Macrophage Colony-Stimulating Factor / metabolism
  • Myeloid-Derived Suppressor Cells / immunology
  • Prognosis
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology
  • Tumor-Associated Macrophages / immunology
  • Up-Regulation / drug effects
  • Up-Regulation / immunology

Substances

  • Amino Acid Transport System y+
  • B7-H1 Antigen
  • CD274 protein, human
  • CSF1 protein, human
  • CSF1 protein, mouse
  • CSF1R protein, human
  • Csf1r protein, mouse
  • HIF1A protein, human
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • IL1B protein, human
  • IL1B protein, mouse
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • Ketoglutaric Acids
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • SLC7A11 protein, human
  • Slc7a11 protein, mouse
  • Macrophage Colony-Stimulating Factor