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IL-1β-induced Elevation of SLC7A11 Promotes Hepatocellular Carcinoma Metastasis through Upregulating PD-L1 and CSF1

Background & aims: Due to paucity of effective treatment options, metastasis is still a major cause for hepatocellular carcinoma (HCC)-associated mortality. Molecular mechanism of inflammation-induced HCC metastasis is largely unknown. 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 patients.

Approach & results: Elevated expression of SLC7A11 was positively correlated with poor tumor differentiation, and higher tumor-nodule-metastasis (TNM) stage, and indicated poor prognosis in human HCC. SLC7A11 increased HIF1α expression through reducing α-ketoglutarate (αKG) level via exporting glutamate. SLC7A11 upregulated programmed death-1-ligand 1 (PD-L1) and colony stimulating factor-1 (CSF1) expression through αKG-HIF1α cascade. SLC7A11 overexpression in HCC cells promoted intratumoral tumour-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) infiltration through CSF1/CSF1R axis, whereas knockdown of CSF1 attenuated SLC7A11-mediated intratumoral TAMs and MDSCs infiltration and HCC metastasis. Depletion of either TAMs or MDSCs decreased SLC7A11-mediated HCC metastasis. Furthermore, combination of CSF1R inhibitor BZL945 and anti-PD-L1 antibody blocked SLC7A11-induced HCC metastasis. In addition, interleukin 1β (IL-1β) upregulated SLC7A11 expression through the IL-1R1/ERK/SP1 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 TAMs and MDSCs infiltration.

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

Related Products

Cat.No. Product Name Information
S7725 Sotuletinib (BLZ945) Sotuletinib (BLZ945) is an orally active, potent and selective CSF-1R inhibitor with IC50 of 1 nM, >1000-fold selective against its closest receptor tyrosine kinase homologs.

Related Targets

CSF-1R