miR-762 Promotes Malignant Development of Head and Neck Squamous Cell Carcinoma by Targeting PHLPP2 and FOXO4
miR-762 Promotes Malignant Development of Head and Neck Squamous Cell Carcinoma by Targeting PHLPP2 and FOXO4
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miR-762通过靶向PHLPP2和FOXO4促进头颈部鳞状细胞癌的恶性发展
DOI：
10.2147/ott.s221442
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发表时间：
2019-01-01
影响因子：
4
通讯作者：
Li, Tie-Jun
中科院分区：
文献类型：
--
作者：
Chen, Shuai;Zhang, Jian-Yun;Li, Tie-Jun
背景头颈部鳞状细胞癌（HNSCC）是世界上最常见的恶性肿瘤之一。本研究探讨了microRNA (miR)-762在调节HNSCC进展中的作用。材料与方法采用定量逆转录聚合酶链式反应（qRT-PCR）检测miR-762在HNSCC组织中的表达水平。通过统计学分析探讨miR-762与HNSCC患者临床病理特征的关系。通过细胞计数（CCK-8）和诱导细胞实验检测细胞增殖和迁移。使用生物信息学工具和芯片筛选miR-762的靶基因，并使用荧光素酶活性报告试验、qRT-PCR和Western blot分析进行确认。通过回避实验检测靶基因是否介导miR-762对HNSCC细胞的影响。通过肿瘤异种移植物验证miR-762的体内作用。结果HNSCC临床标本中miR-762高表达，与TNM分期及预后不良呈正相关。miR-762过表达促进HNSCC细胞体外增殖和迁移。此外，过表达miR-762上调磷酸化AKT （p-AKT）和间质标记物（N-cadherin和vimentin）的表达，抑制上皮标记物（E-cadherin）的表达。miR-762在体内也促进了HNSCC肿瘤的生长。PH结构域、富亮氨酸重复蛋白磷酸酶2 （PHLPP2）和叉头盒O4 （FOXO4）是miR-762的直接靶基因。HNSCC组织中PHLPP2和FOXO4表达水平较低，与miR-762表达呈负相关。此外，PHLPP2和FOXO4的沉默模拟了miR-762对HNSCC细胞的肿瘤促进作用。值得注意的是，PHLPP2和FOXO4的过表达消除了miR-762对细胞增殖和迁移的促肿瘤功能。结论miR-762通过靶向PHLPP2和FOXO4促进HNSCC进展。因此，miR-762可能是HNSCC的潜在诊断或治疗靶点。
Background Head and neck squamous cell carcinoma (HNSCC) is among the most common malignant tumors worldwide. This study, investigated the role of microRNA (miR)-762 in regulating HNSCC progression. Materials and methods The expression levels of miR-762 in HNSCC tissues were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Statistical analyses were performed to investigate the association of miR-762 with clinicopathological features in patients with HNSCC. Cell proliferation and migration were examined by cell counting (CCK-8) and IncuCyte assays. Target genes of miR-762 were screened using bioinformatics tools and microarrays, and confirmed using a luciferase activity reporter assay, qRT-PCR and Western blot analysis. Recuse experiments were performed to detect whether target genes mediated the effects of miR-762 on HNSCC cells. The in vivo effects of miR-762 were verified using tumor xenografts. Results HNSCC clinical specimens showed high expression levels of miR-762, which positively correlated with tumor-node-metastasis (TNM) stage and poor prognosis of HNSCC. miR-762 overexpression promoted the proliferation and migration of HNSCC cells in vitro. In addition, overexpression of miR-762 upregulated the expression of phosphorylated AKT (p-AKT) and mesenchymal markers (N-cadherin and vimentin), but suppressed epithelial marker (E-cadherin) expression. miR-762 also promoted HNSCC tumor growth in vivo. PH domain and leucine-rich repeat protein phosphatase 2 (PHLPP2) and Forkhead box O4 (FOXO4) were direct target genes of miR-762. HNSCC tissues had low expression levels of PHLPP2 and FOXO4, showing a negative correlation with miR-762 expression. Moreover, silencing of PHLPP2 and FOXO4 mimicked the tumor-promotive effects of miR-762 on HNSCC cells. Notably, overexpression of PHLPP2 and FOXO4 abolished the pro-tumoral function of miR-762 on cell proliferation and migration. Conclusion miR-762 promotes HNSCC progression by targeting PHLPP2 and FOXO4. Therefore, miR-762 might be a potential diagnostic or therapeutic target for HNSCC.