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.

Background: The purpose of this study is to perform bioinformatics analysis of autophagy-related genes in gastric cancer, and to construct a multi-gene joint signature for predicting the prognosis of gastric cancer. Methods: GO and KEGG analysis were applied for differentially expressed autophagy-related genes in gastric cancer, and PPI network was constructed in Cytoscape software. In order to optimize the prognosis evaluation system of gastric cancer, we established a prognosis model integrating autophagy-related genes. We used single factor Cox proportional risk regression analysis to screen genes related to prognosis from 204 autophagy-related genes in The Atlas Cancer Genome (TCGA) gastric cancer cohort. Then, the generated genes were applied to the Least Absolute Shrinkage and Selection Operator (LASSO). Finally, the selected genes were further included in the multivariate Cox proportional hazard regression analysis to establish the prognosis model. According to the median risk score, patients were divided into high-risk group and low-risk group, and survival analysis was conducted to evaluate the prognostic value of risk score. Finally, by combining clinic-pathological features and prognostic gene signatures, a nomogram was established to predict individual survival probability. Results: GO analysis showed that the 28 differently expressed autophagy-related genes was enriched in cell growth, neuron death, and regulation of cell growth. KEGG analysis showed that the 28 differently expressed autophagyrelated genes were related to platinum drug resistance, apoptosis and p53 signaling pathway. The risk score was constructed based on 4 genes (GRID2, ATG4D,GABARAPL2, CXCR4), and gastric cancer patients were significantly divided into high-risk and low-risk groups according to overall survival. In multivariate Cox regression analysis, risk score was still an independent prognostic factor (HR = 1.922, 95% CI = 1.573-2.349, P < 0.001). Cumulative curve showed that the survival time of patients with low-risk score was significantly longer than that of patients with high-risk score (P < 0.001). The external data GSE62254 proved that nomograph had a great ability to evaluate the prognosis of individual gastric cancer patients. Conclusions: This study provides a potential prognostic marker for predicting the prognosis of GC patients and the molecular biology of GC autophagy.

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Background Forkhead box C1 (FOXC1), as a member of the FOX family, is important for promote HCC invasion and metastasis. FOX family protein lays a pivotal role in metabolism. ROS is involved in tumor progression and is associated with the expression of lots of transcription factors. We next explored the mechanism underlying FOXC1 modulating the metabolism and ROS hemostasis in HCC. Methods We used amino acids arrays to verify which metabolism is involved in FOXC1-induced HCC. The kits were used to detect the ROS levels in HCC cells with over-expression or down-expression of FOXC1. After identified the downstream target genes and candidate pathway which regulated by FOXC1 during HCC progression in vitro and in vivo, we used western blot, immunohistochemistry, bisulfite genomic sequencing, methylation-specific PCR, chromatin immunoprecipitation analysis and luciferase reporter assays to explore the relationship of FOXC1 and downstream genes. Moreover, the correlation between FOXC1 and target genes and the correlation between target genes and the recurrence and overall survival were analyzed in two independent human HCC cohorts. Results Here, we reported that FOXC1 could inhibit the cysteine metabolism and increase reactive oxygen species (ROS) levels by regulating cysteine metabolism-related genes, cystathionine γ-lyase (CTH). Overexpression of CTH significantly suppressed FOXC1-induced HCC proliferation, invasion and metastasis, while the reduction in cell proliferation, invasion and metastasis caused by the inhibition of FOXC1 could be reversed by knockdown of CTH. Meanwhile, FOXC1 upregulated de novo DNA methylase 3B (DNMT3B) expression to induce DNA hypermethylation of CTH promoter, which resulted in low expression of CTH in HCC cells. Moreover, low levels of ROS induced by N-acetylcysteine (NAC) which is an antioxidant inhibited the cell proliferation, migration, and invasion abilities mediated by FOXC1 overexpression, whereas high levels of ROS induced by L-Buthionine-sulfoximine (BSO) rescued the suppression results mediated by FOXC1 knockdown. Our study demonstrated that the overexpression of FOXC1 that was induced by the ROS dependent on the extracellular regulated protein kinases 1 and 2 (ERK1/2)- phospho-ETS Transcription Factor 1 (p-ELK1) pathway. In human HCC tissues, FOXC1 expression was positively correlated with oxidative damage marker 8-hydroxy-2′-deoxyguanosine (8-OHdG), p-ELK1 and DNMT3B expression, but negatively correlated with CTH expression. HCC patients with positive co-expression of 8-OHdG/FOXC1 or p-ELK1/FOXC1 or FOXC1/DNMT3B had the worst prognosis, whereas HCC patients who had positive FOXC1 and negative CTH expression exhibited the worst prognosis. Conclusion In a word, we clarify that the positive feedback loop of ROS-FOXC1-cysteine metabolism-ROS is important for promoting liver cancer proliferation and metastasis, and this pathway may provide a prospective clinical treatment approach for HCC.