Identification of SRXN1 and KRT6A as Key Genes in Smoking-Related Non-Small-Cell Lung Cancer Through Bioinformatics and Functional Analyses.
Identification of SRXN1 and KRT6A as Key Genes in Smoking-Related Non-Small-Cell Lung Cancer Through Bioinformatics and Functional Analyses.
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通过生物信息学和功能分析鉴定 SRXN1 和 KRT6A 作为吸烟相关非小细胞肺癌的关键基因
DOI：
10.3389/fonc.2021.810301
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发表时间：
2021
影响因子：
4.7
通讯作者：
Yang Q
中科院分区：
文献类型：
--
作者：
Zhou J;Jiang G;Xu E;Zhou J;Liu L;Yang Q
背景肺癌是世界范围内癌症相关死亡的主要原因。尽管吸烟是肺癌的既定危险因素，但几乎没有可靠的非小细胞肺癌(NSCLC)吸烟相关生物标志物可用。对这些生物标记物的更好的理解将进一步发展新的生物标记物靶向治疗，并导致总体患者生存的改善。方法通过生物信息学分析筛选出潜在的靶基因，并通过定量聚合酶链式反应、Western、siRNA、CCK-8、流式细胞仪、裸鼠体内致瘤性实验对其功能进行验证。结果在本研究中，通过对两个基因表达总表(GEO)数据集的整合分析，我们确定了83个吸烟相关基因(SRGs)，并通过分析癌症基因组图谱(TCGA)数据库中的吸烟者NSCLC数据集，确定了27个具有潜在致癌作用的HUB SRG。生存分析显示有3个基因具有潜在的预后价值，即SRXN1、KRT6A和JAKMIP3。单变量COX分析显示SRXN1和KRT6A表达升高与预后显著相关。受试者工作特征(ROC)曲线分析表明SRXN1和KRT6A对吸烟和癌症有较高的诊断价值。定量聚合酶链式反应和Western blotting分别证实了SRXN1和KRT6A在肺癌细胞系和非小细胞肺癌组织中的表达增加。在NSCLC患者中，SRXN1和KRT6A的表达与肿瘤转移分期、有无转移、吸烟史和每日吸烟量有关。此外，抑制SRXN1或KRT6A可抑制A549人肺癌细胞系的活力并促进其凋亡。裸鼠致瘤性分析证实，siRNA介导的SRXN1和KRT6A表达下调抑制了体内肿瘤的生长。结论SRXN1和KRT6A在非小细胞肺癌中起癌基因作用，可能成为吸烟暴露和吸烟者非小细胞肺癌早期诊断和预后的潜在生物标志物，对肺癌的治疗具有重要意义。
Background Lung cancer is the leading cause of cancer-related mortality worldwide. Although cigarette smoking is an established risk factor for lung cancer, few reliable smoking-related biomarkers for non-small-cell lung cancer (NSCLC) are available. An improved understanding of these biomarkers would further the development of new biomarker-targeted therapies and lead to improvements in overall patient survival. Methods We performed bioinformatic analysis to screened potential target genes, then quantitative PCR, western, siRNA, CCK-8, flow cytometry, tumorigenicity assays in nude mice were performed to validated the function. Results In this study, we identified 83 smoking-related genes (SRGs) based on an integration analysis of two Gene Expression Omnibus (GEO) datasets, and 27 hub SRGs with potential carcinogenic effects by analyzing a dataset of smokers with NSCLC in The Cancer Genome Atlas (TCGA) database. A survival analysis revealed three genes with potential prognostic value, namely SRXN1, KRT6A and JAKMIP3. A univariate Cox analysis revealed significant associations of elevated SRXN1 and KRT6A expression with prognosis. A receiver operating characteristic (ROC) curve analysis indicated the high diagnostic value of SRXN1 and KRT6A for smoking and cancer. Quantitative PCR and western blotting validated the increased expression of SRXN1 and KRT6A mRNA and protein, respectively, in lung cancer cell lines and NSCLC tissues. In patients with NSCLC, SRXN1 and KRT6A expression was associated with the tumor–node–metastasis (TNM) stage, presence of metastasis, history of smoking and daily smoking consumption. Furthermore, inhibition of SRXN1 or KRT6A suppressed viability and enhanced apoptosis in the A549 human lung carcinoma cell line. Tumorigenicity assays in nude mice confirmed that the siRNA-mediated downregulation of SRXN1 and KRT6A expression inhibited tumor growth in vivo. Conclusions In summary, SRXN1 and KRT6A act as oncogenes in NSCLC and might be potential biomarkers of smoking exposure and the early diagnosis and prognosis of NSCLC in smokers, which is vital for lung cancer therapy.
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影响因子：
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作者：
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DOI：
10.1080/21691401.2019.1614016
发表时间：
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作者：
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DOI：
10.1016/j.omtn.2017.09.005
发表时间：
2017-12-15
期刊：
Molecular therapy. Nucleic acids
影响因子：
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作者：
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通讯作者：
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