SLC1A5在结直肠癌中的作用及机制

Role and Mechanism of SLC1A5 in Colorectal Cancer

目的研究溶质载体家族1成员5(SLC1A5)在结直肠癌中的表达及与结直肠癌发病的关系。方法使用TIMER2和GEPIA2分析SLC1A5基因表达,通过UALCAN portal和HPA分析SLC1A5蛋白表达。利用UALCAN portal分析SLC1A5表达水平与临床病理参数的关系及结直肠癌中SLC1A5磷酸化蛋白的表达水平。通过Kaplan-Meier Plotter分析结直肠癌中SLC1A5表达水平与预后的关系。使用FunRich 3.1.3预测SLC1A5的转录因子并通过GEPIA2分析SLC1A5表达与转录因子的相关性。采用cBioPortal分析SLC1A5基因变异,TIMER2分析SLC1A5基因表达与免疫浸润之间的关系。通过STRING和GEPIA2获取与SLC1A5相关的基因并进行基因本体(GO)和京都基因和基因组数据库(KEGG)分析。通过GSCA分析SLC1A5表达与药物半数抑制浓度(IC_(50))的关系。结果SLC1A5信使RNA及蛋白在结直肠癌中高表达(P<0.05),SLC1A5表达水平与肿瘤分期及淋巴结转移明显相关(P<0.05)。但是SLC1A5表达水平与结直肠癌患者预后无明显相关性(P=0.088)。E2F转录因子1可正调控SLC1A5的表达(r=0.14,P=0.0083)。突变是结直肠癌中SLC1A5基因最主要的变异类型,而错义突变又是基因突变的主要类型。结肠癌中S503位点磷酸化水平无明显增强(P=0.102)。但是在直肠癌中肿瘤相关成纤维细胞的估计浸润值与SLC1A5的表达水平呈负相关(P=0.0249)。KEGG数据提示SLC1A5在肿瘤发病中的作用可能与耶尔森菌感染和炎症介质对瞬时受体电位通道的调节有关,GO富集分析数据进一步显示,这些基因大多与蛋白质代谢、外泌体、蛋白质丝氨酸/苏氨酸激酶活性和氨肽酶活性有关。IC_(50)数据显示17-AAG、PD-0325901、Trametinib、BMS-345541、BMS-536924、SCH-79797、fluorouracil和pevonedistat可显著抑制SLC1A5基因表达(P<0.05)。结论SLC1A5在结直肠癌中高表达并与结直肠癌的发生发展密切相关,可作为结直肠癌治疗的潜在作用靶点。

Objective To explore the expression of solute carrier family 1 member 5(SLC1A5)in colorectal cancer and its relationship with the pathogenesis of colorectal cancer.Methods TIMER2 and GEPIA2 were used to analyze SLC1A5 gene expression,and UALCAN portal and HPA were used to analyze SLC1A5 protein expression.UALCAN portal was also used to correlate SLC1A5 expression with clinicopathologic parameter and analyze the expression of the SLC1A5 phosphorylated protein in colorectal cancer.Relationship between the expression of SLC1A5 and prognosis was analyzed by Kaplan-Meier Plotter.FunRich 3.1.3 was used to screen transcription factors of SLC1A5 and GEPIA2 was used to analysis the relationship between the expression of SLC1A5 and the transcription factors.cBioPortal was used to analyze genetic variaation,and the correlation of SLC1A5 expression and immune infiltration was analyzed by TIMER2.SLC1A5-relevant genes were obtained through STRING and GEPIA2,and gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)analyses were performed.The relationship between SLC1A5 expression and half inhibitory concentration(IC_(50))was analyzed by GSCA.Results SLC1A5 mRNA and protein were highly expressed in colorectal cancer(P<0.05),and SLC1A5 expression level was significantly correlated with tumor stage and lymph node metastasis(P<0.05).But the expression of SLC1A5 had no obvious correlation with prognosis in colorectal cancer patients(P=0.088).Transcription factor E2F1 could positively regulate the expression of SLC1A5(r=0.14,P=0.0083).Mutation was the major variant type of SLC1A5 in colorectal cancer,and missense mutation of SLC1A5 was the main type of the mutation.There was no enhanced phosphorylation level of S503 locus in colorectal cancer observed(P=0.102).But a negative correlation between estimated infiltration value of tumor-associated fibroblasts and SLC1A5 expression in rectal cancer was observed(P=0.0249).The KEGG data suggested that Yersinia infection and inflammatory mediator regulation of transient receptor potential channel might be involved in the role of SLC1A5 in tumor pathogenesis,and the GO enrichment analysis data further indicated that most of these genes were linked to the protein metabolism,exosomes,protein serine/threonine kinase activity and aminopeptidase activity.IC_(50)data showed 17-AAG,PD-0325901,Trametinib,BMS-345541,BMS-536924,SCH-79797,fluorouracil and pevonedistat significantly inhibited SLC1A5 expression(P<0.05).Conclusion SLC1A5 is highly expressed in colorectal cancer and is closely related to the occurrence and development of colorectal cancer,which can be a potential target for colorectal cancer treatment.