In:
Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 74, No. 6 ( 2021-12), p. 3174-3193
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0270-9139
,
1527-3350
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2021
detail.hit.zdb_id:
1472120-X
