长链非编码 RNA FOXD2-AS1 通过靶向 miR-185-5p/CCND2 轴促进胶质瘤恶性肿瘤发生和肿瘤发生。
Long noncoding RNA FOXD2-AS1 promotes glioma malignancy and tumorigenesis via targeting miR-185-5p/CCND2 axis.
机构信息
Department of Neurosurgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China.
Department of The Clinical Laboratory, The Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China.
出版信息
J Cell Biochem. 2019 Jun;120(6):9324-9336. doi: 10.1002/jcb.28208. Epub 2018 Dec 5.
Glioma is the most aggressive malignant tumor in the adult central nervous system. Abnormal long noncoding RNA (lncRNA) FOXD2-AS1 expression was associated with tumor development. However, the possible role of FOXD2-AS1 in the progression of glioma is not known. In the present study, we used in vitro and in vivo assays to investigate the effect of abnormal expression of FOXD2-AS1 on glioma progression and to explore the mechanisms. FOXD2-AS1 was upregulated in glioma tissue, cells, and sphere subpopulation. Upregulation of FOXD2-AS1 was correlated with poor prognosis of glioma. Downregulation of FOXD2-AS1 decreased cell proliferation, migration, invasion, stemness, and epithelial-mesenchymal transition (EMT) in glioma cells and inhibited tumor growth in transplanted tumor. We also revealed that FOXD2-AS1 was mainly located in cytoplasm and microRNA (miR)-185-5p both targeted FOXD2-AS1 and CCND2 messenger RNA (mRNA) 3'-untranslated region (3'-UTR). miR-185-5p was downregulated in glioma tissue, cells, and sphere subpopulation. Downregulation of miR-185-5p was closely correlated with poor prognosis of glioma patients. In addition, miR-185-5p mimics decreased cell proliferation, migration, invasion, stemness, and EMT in glioma cells. CCND2 was upregulated in glioma tissue, cells, and sphere subpopulation. Upregulation of CCND2 was closely correlated with poor prognosis of glioma patients. CCND2 knockdown decreased cell proliferation, migration, invasion, and EMT in glioma cells. In glioma tissues, CCND2 expression was negatively associated with miR-185-5p, but positively correlated with FOXD2-AS1. FOXD2-AS1 knockdown and miR-185-5p mimics decreased CCND2 expression. Inhibition of miR-185-5p suppressed FOXD2-AS1 knockdown-induced decrease of CCND2 expression. Overexpression of CCND2 suppressed FOXD2-AS1 knockdown-induced inhibition of glioma malignancy. Taken together, our findings highlight the FOXD2-AS1/miR-185-5p/CCND2 axis in the glioma development.
神经胶质瘤是成人中枢神经系统中最具侵袭性的恶性肿瘤。异常长链非编码 RNA（lncRNA）FOXD2-AS1 的表达与肿瘤的发生发展有关。然而，FOXD2-AS1 在神经胶质瘤进展中的可能作用尚不清楚。在本研究中，我们通过体外和体内实验研究了异常表达 FOXD2-AS1 对神经胶质瘤进展的影响，并探讨了其机制。FOXD2-AS1 在神经胶质瘤组织、细胞和球体亚群中上调。FOXD2-AS1 的上调与神经胶质瘤的不良预后相关。下调 FOXD2-AS1 可降低神经胶质瘤细胞的增殖、迁移、侵袭、干性和上皮-间充质转化（EMT），并抑制移植瘤的生长。我们还揭示了 FOXD2-AS1 主要位于细胞质中，miR-185-5p 可靶向 FOXD2-AS1 和 CCND2 信使 RNA（mRNA）3'-非翻译区（3'-UTR）。miR-185-5p 在神经胶质瘤组织、细胞和球体亚群中下调。miR-185-5p 的下调与神经胶质瘤患者的不良预后密切相关。此外，miR-185-5p 模拟物可降低神经胶质瘤细胞的增殖、迁移、侵袭、干性和 EMT。CCND2 在神经胶质瘤组织、细胞和球体亚群中上调。CCND2 的上调与神经胶质瘤患者的不良预后密切相关。CCND2 敲低可降低神经胶质瘤细胞的增殖、迁移、侵袭和 EMT。在神经胶质瘤组织中，CCND2 的表达与 miR-185-5p 呈负相关，与 FOXD2-AS1 呈正相关。FOXD2-AS1 敲低和 miR-185-5p 模拟物降低了 CCND2 的表达。抑制 miR-185-5p 可抑制 FOXD2-AS1 敲低诱导的 CCND2 表达降低。过表达 CCND2 可抑制 FOXD2-AS1 敲低诱导的神经胶质瘤恶性抑制作用。总之，我们的研究结果强调了 FOXD2-AS1/miR-185-5p/CCND2 轴在神经胶质瘤发生发展中的作用。
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