MiR-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor LEF1

Abstract

Abstract. The invasive behavior of glioblastoma multiforme (GBM) cells is one of the most important reasons for the poor prognosis of this cancer. For invasion, tumor cells must acquire an ability to digest the extracellular matrix and infiltrate the normal tissue bordering the tumor. Preventing this by altering effector molecules can significantly improve a patient's prognosis. Accumulating evidence suggests that miRNAs are involved in multiple biological functions, including cell invasion, by altering the expression of multiple target genes. The expression levels of miR-218 correlate with the invasive potential of GBM cells. In this study, we found that miR-218 expression was low in glioma tissues, especially in GBM. The data showed an inverse correlation in 60 GBM tissues between the levels of miR-218 and MMP mRNAs (MMP-2, -7 and -9). Additionally, ectopic expression of miR-218 suppressed the invasion of GBM cells whereas inhibition of miR-218 expression enhanced the invasive ability. Numerous members of the MMP family are downstream effectors of the Wnt/LEF1 pathway. Target prediction databases and luciferase data showed that LEF1 is a new direct target of miR-218. Importantly, western blot assays demonstrated that miR-218 can reduce protein levels of LEF1 and MMP-9. We, therefore, hypothesize that miR-218 directly targets LEF1, resulting in reduced synthesis of MMP-9. Results suggest that miR-218 is involved in the invasive behavior of GBM cells and by targeting LEF1 and blocking the invasive axis, miR-218-LEF1-MMPs, it may be useful for developing potential clinical strategies. IntroductionGBM (WHO-grade IV) is the most malignant and frequent brain tumor and has the worst prognosis of any cancer. Despite advances in treatment by surgery combined with radiotherapy or chemotherapy, patients with GBM have a mean survival of only 14.6 months (1). Therefore, new therapeutic targets are urgently needed. A formidable difficulty in treating GBM is that tumor cells diffuse and infiltrate the normal peripheral tissue, therefore it is not possible to completely dissect out and remove the tumor. Degradation of extracellular matrix (ECM) is the defining step in tumor cell invasion and members of the matrix metalloproteinase family (MMPs) have crucial roles in regulating this process (2-4). Thus, understanding and blocking the invasive process may be an effective strategy for treating GBM.The recent discovery of miRNAs is a major advance. Accumulating evidence suggests that miRNAs are involved in multiple biological functions, including cell invasion, by altering the expression of multiple target genes. They bind to the 3' untranslated region (UTR) of target messenger RNAs (mRNAs) to suppress translation or induce degradation of these mRNAs. The roles different miRNAs play have been recently expounded in numerous human tumors as detailed below.Accumulated evidence shows that downregulation of miR-218 can enhance tumor cell invasion and proliferation in several kinds of solid tumors (5,6). In this study, we have identifi...

miR-218 inhibits the proliferation of glioma U87 cells through the inactivation of the CDK6/cyclin D1/p21Cip1/Waf1 pathway

“…The expression of lymphoid enhancer-binding factor 1 (LEF1) and MMP-9 in the high-grade glioma group was extremely high, while the expression in the low-grade glioma group was extremely low, and the expression of LEF1 and MMP-9 was negatively correlated with the expression of miR-218. Overexpression of miR-218 has been found to inhibit the Wnt/LEF1 signaling pathways that lead to a reduction in MMP-9 synthesis and inhibit tumor invasion (16). The abnormal expression of miR-218 in glioma cells decreased, but abnormal increase CDK6 expression, the expression level of both negatively correlated.…”

“…Out of these miRNA molecules, miRNA 218 (miR-218) has been revealed to be downregulated in human glioblastoma multiforme (GBM) specimens compared with the adjacent brain tissue that is devoid of tumor cells (11)(12)(13)(14). Accumulated data have demonstrated that the upregulation of miR-218 is able to inhibit tumor cell invasion and proliferation in glioma cells by altering the expression of multiple target genes (14)(15)(16)(17).…”

miR-218 suppresses tumor growth and enhances the chemosensitivity of esophageal squamous cell carcinoma to cisplatin

“…It has been shown that miR-218 expression is downregulated in many tumors including ESCC (15)(16)(17)(18)(19)(20) and is involved in cancer initiation and development (15)(16)(17)(18)(19)(20)(21)(22) SOT (38), Rob1 receptor (39) as well as LAmb3 (40), which are involved in several different signaling pathways, suggesting that miR-218 is a tumor suppressor miRNA and plays a crucial role in the initiation, development and metastasis of tumors. Therefore, we reasonably speculated that miR-218 suppresses the tumor growth of ESCC in vitro and in vivo by regulating multiple target genes.…”

“…microRNA-218 (miR-218) is a recently discovered miRNA and is downregulated in several types of cancer, such as gastric cancer (15,16), cervical squamous cell carcinoma (17), medulloblastoma (18), lung cancer (19) and glioblastoma (20). Accumulating evidence demonstrates that miR-218 acts as a tumor suppressor and confers an inhibitory effect on cancer cell proliferation, migration and invasion by targeting genes (15)(16)(17)(18)(19)(20)(21)(22). In particular, recently studies have demonstrated that overexpression of miR-218 increased chemosensitivity to cisplatin (CDDP) in cervical cancer cells (23).…”

miRNA-218 Inhibits Osteosarcoma Cell Migration and Invasion by Down-regulating of TIAM1, MMP2 and MMP9

“…Study also showed that miRNA-218 inhibit the head and neck squamous cell carcinoma by targeting laminin-332 (Kinoshita et al, 2012). Data from can reverse high invasiveness of glioblastoma cells by targeting oncogenic transcription factor LEF1 (Liu et al, 2012). Study from Alajez et al (2011) demonstrated that miR-218 suppresses nasopharyngeal cancer progression by regulating the surviving and SLIT2-ROBO1 pathways.…”