微小 RNA-22-3p 靶向 TP53 在肺腺癌中的临床意义及机制。
The clinical significance and mechanism of microRNA-22-3p targeting TP53 in lung adenocarcinoma.
机构信息
Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
出版信息
Technol Health Care. 2023;31(5):1691-1707. doi: 10.3233/THC-220494.
BACKGROUND
At present, studies on MircoRNA-22-3p (miR-22-3p) in lung adenocarcinoma use a single method, lack multi-center validation and multi-method validation, and there is no big data concept to predict and validate target genes.
OBJECTIVE
To investigate the expression, potential targets and clinicopathological significance of miR-22-3p in lung adenocarcinoma (LUAD) tissues.
METHODS
LUAD formalin-fixed paraffin-embedded (FFPE) tumors and adjacent normal lung tissues were collected for real-time quantitative polymerase chain reaction (RT-qPCR). Collect miR-22-3p in LUAD and non-cancer lung tissue from high-throughput datasets, standardized mean difference (SMD) and area under the curve (AUC) of the comprehensive receiver operating curve (summary receiver operating characteristic cure, sROC curve) were calculated. Cell function experiments on A549 cells transfected with LV-hsa-miR-22-3p. Target genes were predicted by the miRwalk2.0 website and the resulting target genes were subjected to Gene Ontology (GO) pathway enrichment analysis and constructed to protein-protein interaction network. Finally, the protein expression level of the key gene TP53 was validated by searching The Human Protein Atlas (THPA) database to incorporate TP53 immunohistochemical results in LUAD.
RESULTS
RT-qPCR result from 41 pairs of LUAD and adjacent lung tissues showed that miR-22-3p was downregulated in LUAD (AUC = 0.6597, p= 0.0128). Globally, a total of 838 LUADs and 494 non-cancerous lung tissues were included, and were finally combined into 14 platforms. Compared with noncancerous tissue, miR-22-3p expression level was significantly reduced in LUAD tissue (SMD =-0.32, AUC = 0.72l); cell function experiments showed that miR-22-3p has inhibitory effects on cell proliferation, migration and invasion, and has promotion effect on apoptosis. Moreover, target genes prediction, GO pathway enrichment analysis and PPI network exhibited TP53 as a key gene of target gene of miR-22-3p; at last, a total of 114 high-throughput datasets were included, including 3897 LUADs and 2993 non-cancerous lung tissues, and were finally combined into 37 platforms. Compared with noncancerous tissue, TP53 expression level was significantly increased in LUAD (SMD = 0.39, p< 0.01) and it was verified by the protein expression data from THPA.
CONCLUSION
Overexpression of miR-22-3p may inhibit LUAD cell proliferation, migration and invasion through TP53, and promote cell apoptosis.
背景
目前，关于肺腺癌中 MicroRNA-22-3p（miR-22-3p）的研究仅使用了单一方法，缺乏多中心验证和多方法验证，并且没有大数据概念来预测和验证靶基因。
目的
探讨 miR-22-3p 在肺腺癌（LUAD）组织中的表达、潜在靶基因及临床病理意义。
方法
收集 41 对 LUAD 及相邻正常肺组织的实时定量聚合酶链反应（RT-qPCR）结果。从高通量数据集收集 miR-22-3p 在 LUAD 和非癌性肺组织中的表达，计算标准化均数差（SMD）和综合接收者操作特征曲线（summary receiver operating characteristic cure，sROC 曲线）下面积（AUC）。用 LV-hsa-miR-22-3p 转染 A549 细胞进行细胞功能实验。通过 miRwalk2.0 网站预测靶基因，并对预测的靶基因进行基因本体论（GO）通路富集分析，构建蛋白-蛋白相互作用网络。最后，通过搜索人类蛋白质图谱（THPA）数据库验证关键基因 TP53 的蛋白表达水平，将 LUAD 中的 TP53 免疫组织化学结果纳入其中。
结果
41 对 LUAD 及相邻肺组织的 RT-qPCR 结果显示，miR-22-3p 在 LUAD 中表达下调（AUC=0.6597，p=0.0128）。总共纳入 838 例 LUAD 和 494 例非癌性肺组织，最终结合为 14 个平台。与非癌性组织相比，miR-22-3p 在 LUAD 组织中的表达水平明显降低（SMD=-0.32，AUC=0.72l）；细胞功能实验表明，miR-22-3p 对细胞增殖、迁移和侵袭具有抑制作用，对细胞凋亡具有促进作用。此外，靶基因预测、GO 通路富集分析和 PPI 网络显示 TP53 是 miR-22-3p 靶基因的关键基因；最后，共纳入 114 个高通量数据集，包括 3897 例 LUAD 和 2993 例非癌性肺组织，最终结合为 37 个平台。与非癌性组织相比，TP53 的表达水平在 LUAD 中明显升高（SMD=0.39，p<0.01），并通过 THPA 的蛋白质表达数据得到验证。
结论
miR-22-3p 的过表达可能通过 TP53 抑制 LUAD 细胞的增殖、迁移和侵袭，并促进细胞凋亡。
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