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

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 myeloid­derived 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.

Glutamine Metabolism Regulators Associated with Cancer Development and the Tumor Microenvironment: A Pan-Cancer Multi-Omics Analysis

“…The expression of PD-L1 was mediated via the nuclear factor-kappa B (NF-kB) signaling pathway, which was activated by the reduction in GSH levels [42]. Upregulated SLC7A11 promoted the expression of PD-L1 and CSF1 through the αKG/HIF1α axis, which further recruited TAMs and MDSCs infiltration [43]. These results suggested that targeting these regulators may provide a way in which to reverse the cold immune microenvironment and enhance the antitumor effects.…”

Construction and Validation of a Combined Ferroptosis and Hypoxia Prognostic Signature for Hepatocellular Carcinoma

“…Previous studies have shown that the upregulation of SLC7A11 is associated with poor prognosis of HCC, while the downregulation of SLC7A11 can inhibit the growth of HCC (Guo et al, 2011;Kinoshita et al, 2013). In addition, He et al showed that SLC7A11 can up-regulate the expression of PD-L1 and CSF1, and promote the infiltration of TAMs and MDSCs in HCC, as well as the metastasis of HCC (He et al, 2021). STC2 is the target gene of HIF-1 and has been proved to be a prognostic marker of ovarian cancer, breast cancer, and kidney cancer (Chang et al, 2003;Buckanovich et al, 2007;Esseghir et al, 2007).…”

The Role of Cystine/Glutamate Antiporter SLC7A11/xCT in the Pathophysiology of Cancer

“…This αKG- HIF1α cascade upregulates PD-L1 and colony-stimulating factor-1 (CSF1), which further increase HCC metastasis via infiltration of tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs). Either depletion of TAMs or MDSCs, treatment with a CSF1 inhibitor, an anti-PD-L1 antibody or Anakinra (an IL1β inhibitor), or SLC7A11 knockdown, all result in a reduction in HCC metastasis ( 114 ). xCT inhibition by sulfasalazine or through siRNA targeting SLC7A11 leads to reduced cell proliferation in vitro and in-vivo via reduction in GSH levels and an increase in ROS by inhibiting the CD44v9-SLC7A11 interaction ( 111 , 113 ).…”