Liao Yan, Weng Junmei, Chen Lian, Hu Nan, Yuan Xun, Wang Jianhua, He Feng, Cai Yixin, Huang Qin, Wang Jianing, Huang Liu
Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
The Reproductive Medical Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.
Front Genet. 2022 Sep 16;13:911378. doi: 10.3389/fgene.2022.911378. eCollection 2022.
Tumor cells outcompete T cells for methionine via overexpressing SLC43A2, causing T cells exhaustion. We explored the influence of SLC43A2 on tumor immune microenvironment (TIME), immune-related genes (IRGs) and the prognosis of liver hepatocellular carcinoma (LIHC) patients. The TCGA-LIHC dataset ( = 374) and the ICGC-LIRI-JP-LIHC ( = 231) datasets were used as training and validation cohort, respectively. IRGs were obtained from ImmPort. Statistical analyses were performed using R (V 4.0.5). Online databases such as GEPIA, GSCALite, the Kaplan-Meier plotter, KEGG, TIMER2, and CMap were used for differential expression, immune infiltration, functional enrichment, survival, and drug-induced gene perturbation analysis. SLC43A2 expression was higher in LIHC, correlated with worse survival, but could not predict prognosis of LIHC separately (AUC = 0.467). SLC43A2 positively correlated with immune exhaustion markers (all < 0.001) and with increased infiltration of Tregs, macrophages and myeloid-derived suppressor cells (MDSC) (all < 0.05). SLC43A2 may regulate 120 IRGs. A prognostic risk score model was developed using the TCGA-LIHC cohort and validated by the ICGC-LIRI-JP cohort. Arachidonic acid, SB-202190 and guanethidine were identified as possible immunomodulators pharmacologically targeting SLC43A2 in LIHC. SLC43A2 may create suppressive tumor microenvironment and regulate related IRGs, thus affecting the prognosis of LIHC. Arachidonic acid, SB-202190, and guanethidine may be worthy of further study as immunomodulators on SLC43A2.
肿瘤细胞通过过度表达SLC43A2与T细胞竞争蛋氨酸，导致T细胞耗竭。我们探讨了SLC43A2对肿瘤免疫微环境（TIME）、免疫相关基因（IRGs）以及肝细胞癌（LIHC）患者预后的影响。分别将TCGA-LIHC数据集（n = 374）和ICGC-LIRI-JP-LIHC（n = 231）数据集用作训练和验证队列。IRGs从ImmPort获取。使用R（V 4.0.5）进行统计分析。诸如GEPIA、GSCALite、Kaplan-Meier绘图仪、KEGG、TIMER2和CMap等在线数据库用于差异表达、免疫浸润、功能富集、生存和药物诱导基因扰动分析。SLC43A2在LIHC中表达较高，与较差的生存率相关，但不能单独预测LIHC的预后（AUC = 0.467）。SLC43A2与免疫耗竭标志物呈正相关（均P < 0.001），并与调节性T细胞、巨噬细胞和髓系来源抑制细胞（MDSC）浸润增加相关（均P < 0.05）。SLC43A2可能调节120个IRGs。使用TCGA-LIHC队列建立了预后风险评分模型，并通过ICGC-LIRI-JP队列进行验证。花生四烯酸、SB-202190和胍乙啶被确定为可能在药理学上靶向LIHC中SLC43A2的免疫调节剂。SLC43A2可能会创建抑制性肿瘤微环境并调节相关IRGs，从而影响LIHC的预后。花生四烯酸、SB-202190和胍乙啶作为针对SLC43A2的免疫调节剂可能值得进一步研究。
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