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

作者：Qin He, Mei Liu, Wenjie Huang, Xiaoping Chen, Bixiang Zhang, Tongyue Zhang, Yijun Wang, Danfei Liu, Meng Xie, Xiaoyu Ji, Mengyu Sun, Dean Tian, Limin Xia · 发表于：Hepatology · 年份：2021 · DOI：10.1002/hep.32062 · 被引用次数：192 · 研究领域：Immune cells in cancer、Ferroptosis and cancer prognosis、Neuroinflammation and Neurodegeneration Mechanisms

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 k...