Marisetty Anantha, Wei Jun, Kong Ling-Yuan, Ott Martina, Fang Dexing, Sabbagh Aria, Heimberger Amy B
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cancers (Basel). 2020 Dec 17;12(12):3813. doi: 10.3390/cancers12123813.
MiRNAs can silence a wide range of genes, which may be an advantage for targeting heterogenous tumors like glioblastoma. Osteopontin (OPN) plays both an oncogenic role in a variety of cancers and can immune modulate macrophages. We conducted a genome wide profiling and bioinformatic analysis to identify miR-181a/b/c/d as potential miRNAs that target OPN. Luciferase assays confirmed the binding potential of miRNAs to OPN. Expression levels of miR-181a/b/c/d and OPN were evaluated by using quantitative real-time PCR and enzyme-linked immunosorbent assay in mouse and human glioblastomas and macrophages that showed these miRNAs were downregulated in Glioblastoma associated CD11b+ cells compared to their matched blood CD14b+ cells. miRNA mimicking and overexpression using lentiviruses showed that MiR-181a overexpression in glioblastoma cells led to decreased OPN production and proliferation and increased apoptosis in vitro. MiR-181a treatment of immune competent mice bearing intracranial glioblastoma demonstrated a 22% increase in median survival duration relative to that of control mice.
微小RNA（miRNA）可以使多种基因沉默，这对于靶向胶质母细胞瘤等异质性肿瘤可能是一个优势。骨桥蛋白（OPN）在多种癌症中发挥致癌作用，并且可以调节巨噬细胞的免疫功能。我们进行了全基因组分析和生物信息学分析，以确定miR-181a/b/c/d是靶向OPN的潜在miRNA。荧光素酶检测证实了miRNA与OPN的结合潜力。通过定量实时PCR和酶联免疫吸附测定法评估了miR-181a/b/c/d和OPN在小鼠和人类胶质母细胞瘤及巨噬细胞中的表达水平，结果显示与匹配的血液CD14b+细胞相比，这些miRNA在胶质母细胞瘤相关的CD11b+细胞中表达下调。使用慢病毒进行miRNA模拟和过表达实验表明，胶质母细胞瘤细胞中miR-181a过表达导致体外OPN产生减少、细胞增殖降低以及细胞凋亡增加。对患有颅内胶质母细胞瘤的免疫健全小鼠进行miR-181a治疗，结果显示相对于对照小鼠，中位生存时间增加了22%。
