Huo Zirong, Li Xiaoguang, Zhou Jieyu, Fan Yuqin, Wang Zhentao, Zhang Zhihua
Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Ear Institute Shanghai Jiaotong University, Shanghai, China.
Cancer Cell Int. 2021 Oct 26;21(1):564. doi: 10.1186/s12935-021-02251-w.
DNA methylation and miRNA-target genes play an important part in the early development of various tumors and have been studied as tumor biomarkers. Although previous studies have reported a cluster of molecular events (such as aberrant alterations of genomics and epigenetics), little is known of the potential biomarkers for early diagnosis and prognostic evaluation in head and neck squamous cell carcinoma (HNSCC).
Multiple bioinformatics tools based on The Cancer Genome Atlas (TCGA) database and clinical samples were applied to evaluate the beneficial biomarkers in HNSCC. We focused on the role of plasminogen activator urokinase (PLAU), including diagnostic and prognostic significance, gene expression analysis, aberrant DNA methylation characteristics, interaction of miRNAs and associated signaling pathways.
We found that PLAU was aberrantly upregulated in HNSCC, regardless of the mRNA or protein level. The results of receiver operating characteristic (ROC) curve and Cox regression analysis revealed that PLAU was a diagnostic and independent prognostic factor for patients with HNSCC. Hypomethylation of PLAU was closely related to poor survival in HNSCC. Additionally, miR-23b-3p was predicted to target PLAU and was significantly downregulated in HNSCC tissues. Therefore, our findings suggested that PLAU functioned as a promoter in the pathological process of HNSCC. DNA hypomethylation and downregulation of miR-23b-3p were associated with PLAU overexpression. Finally, our findings provided evidence of a significant interaction between PLAU-target and miRNAs-target pathways, indicating that miR-23b-3p suppresses malignant properties of HNSCC by targeting PLAU via Ras/MAPK and Akt/mTOR signaling pathways.
PLAU is overexpressed and may serve as an independent diagnostic and prognostic biomarker in HNSCC. Hypomethylation and downregulation of miR-23b-3p might account for the oncogenic role of PLAU in HNSCC.
DNA甲基化和微小RNA（miRNA）靶向基因在各种肿瘤的早期发展中起着重要作用，并已作为肿瘤生物标志物进行研究。尽管先前的研究报道了一系列分子事件（如基因组学和表观遗传学的异常改变），但对于头颈部鳞状细胞癌（HNSCC）早期诊断和预后评估的潜在生物标志物知之甚少。
应用基于癌症基因组图谱（TCGA）数据库和临床样本的多种生物信息学工具，评估HNSCC中的有益生物标志物。我们重点研究了尿激酶型纤溶酶原激活剂（PLAU）的作用，包括诊断和预后意义、基因表达分析、异常DNA甲基化特征、miRNA相互作用及相关信号通路。
我们发现，无论mRNA还是蛋白质水平，PLAU在HNSCC中均异常上调。受试者工作特征（ROC）曲线和Cox回归分析结果显示，PLAU是HNSCC患者的诊断和独立预后因素。PLAU的低甲基化与HNSCC患者的不良生存密切相关。此外，预测miR-23b-3p靶向PLAU，且在HNSCC组织中显著下调。因此，我们的研究结果表明，PLAU在HNSCC的病理过程中起促进作用。DNA低甲基化和miR-23b-3p下调与PLAU过表达相关。最后，我们的研究结果提供了PLAU靶向和miRNA靶向途径之间显著相互作用的证据，表明miR-23b-3p通过Ras/丝裂原活化蛋白激酶（MAPK）和Akt/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路靶向PLAU，从而抑制HNSCC的恶性特性。
PLAU过表达，可能作为HNSCC的独立诊断和预后生物标志物。miR-23b-3p的低甲基化和下调可能解释了PLAU在HNSCC中的致癌作用。
