MiR-218 sensitizes glioma cells to apoptosis and inhibits tumorigenicity by regulating ECOP-mediated suppression of NF-κB activity

Xia, Hongping; Yan, Yukui; Hu, Minghua; Wang, Yaxian; Wang, Yongsheng; Dai, Yi; Chen, Jianming; Di, Guangfu; Chen, Xiaobing; Jiang, Xiaochun

doi:10.1093/neuonc/nos296

Cited by 74 publications

(70 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although recent studies indicate that increased miR-218 expression impacts cell viability in nasopharyngeal cancer and GBM cells (20,21), a role for miR-218 in conferring chemoresistance was not known. To test whether miR-218 has such a role, we used a gain-of-function approach by restoring miR-218 expression in GSCs or GBM cell lines.…”

Section: Resultsmentioning

confidence: 99%

miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma

Mathew

Skuli

Mucaj

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) and the mesenchymal GBM subtype in particular are highly malignant tumors that frequently exhibit regions of severe hypoxia and necrosis. Because these features correlate with poor prognosis, we investigated microRNAs whose expression might regulate hypoxic GBM cell survival and growth. We determined that the expression of microRNA-218 (miR-218) is decreased significantly in highly necrotic mesenchymal GBM, and orthotopic tumor studies revealed that reduced miR-218 levels confer GBM resistance to chemotherapy. Importantly, miR-218 targets multiple components of receptor tyrosine kinase (RTK) signaling pathways, and miR-218 repression increases the abundance and activity of multiple RTK effectors. This elevated RTK signaling also promotes the activation of hypoxia-inducible factor (HIF), most notably HIF2α. We further show that RTK-mediated HIF2α regulation is JNK dependent, via jun proto-oncogene. Collectively, our results identify an miR-218-RTK-HIF2α signaling axis that promotes GBM cell survival and tumor angiogenesis, particularly in necrotic mesenchymal tumors.

show abstract

Section: Resultsmentioning

confidence: 99%

miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma

Mathew

Skuli

Mucaj

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Two primary glioblastoma cell cultures (GBM1 and GBM2) were derived from glioma patient samples as described previously. 29 The primary glioma cells were cultured as follows: patient biopsies were immediately dissociated by trypsinization and subsequently were cultured in Neurobasal Medium (Invitrogen), with 1× B-27 and 1× GlutaMax I (Invitrogen). All medium was supplemented with 10% FBS (Invitrogen) and 100 U/ml penicillin/streptomycin (Sigma).…”

Section: Methods Cell Lines and Tissue Samplesmentioning

confidence: 99%

Increased level of H19 long noncoding RNA promotes invasion, angiogenesis, and stemness of glioblastoma cells

Jiang

Yan

et al. 2016

JNS

Self Cite

157

View full text Add to dashboard Cite

M alignant gliomas are the most common type of primary malignant brain tumor, and more than half of all gliomas are glioblastomas (Grade IV astrocytoma), one of the most aggressive and lethal types of brain tumor. Glioblastoma cells easily infiltrate into the normal cerebral cortex, ultimately resulting in the death of the patient. Well-defined risk factors for glioblastoma include radiation exposure and certain genetic syndromes. 21Several molecular and genomic datasets have recently been generated that have allowed identification of at least 4 subtypes of glioblastoma: classical, mesenchymal, proneural, and neural.14 Previous studies in glioblastoma geabbreviatioNs FBS = fetal bovine serum; HCC = hepatocellular carcinoma; HUVEC = human umbilical vein endothelial cell; lncRNA = long noncoding RNA; ncRNA = noncoding RNA; RT-qPCR = real-time quantitative reverse transcription polymerase chain reaction; SD = standard deviation. 3 Department of Respiratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing; and 4 Department of Oncology, The Second Affiliated Hospital of Suzhou University, Suzhou, China obJective Increased levels of H19 long noncoding RNA (lncRNA) have been observed in many cancers, suggesting that overexpression of H19 may be important in the development of carcinogenesis. However, the role of H19 in human glioblastoma is still unclear. The object of this study was to examine the level of H19 in glioblastoma samples and investigate the role of H19 in glioblastoma carcinogenesis. methods Glioblastoma and nontumor brain tissue specimens were obtained from tissue obtained during tumor resection in 30 patients with glioblastoma. The level of H19 lncRNA was detected by real-time quantitative reverse transcription polymerase chain reaction. The role of H19 in invasion, angiogenesis, and stemness of glioblastoma cells was then investigated using commercially produced cell lines (U87 and U373). The effects of H19 overexpression on glioblastoma cell invasion and angiogenesis were detected by in vitro Matrigel invasion and endothelial tube formation assay. The effects of H19 on glioblastoma cell stemness and tumorigenicity were investigated by neurosphere formation and an in vivo murine xenograft model. results The authors found that H19 is significantly overexpressed in glioblastoma tissues, and the level of expression was associated with patient survival. In the subsequent investigations, the authors found that overexpression of H19 promotes glioblastoma cell invasion and angiogenesis in vitro. Interestingly, H19 was also significantly overexpressed in CD133 + glioblastoma cells, and overexpression of H19 was associated with increased neurosphere formation of glioblastoma cells. Finally, stable overexpression of H19 was associated with increased tumor growth in the murine xenograft model. coNclusioNs The results of this study suggest that increased expression of H19 lncRNA promotes invasion, angiogenesis, stemness, and tumorigenicity of glioblastoma cells. Taken together, the...

show abstract

“…However, miR-218 expression was lower in A549 cells ( Figure 1A & 1B). Previous studies have indicated that Robo1 is a downstream target of miR-218 [14] and that Ecop is a key functional target of miR-218 [10]. Therefore, Robo1 and Ecop mRNA expression was examined in the same human lung adenocarcinoma cell lines and showed that Robo1 and Ecop was in lower expression in A549 cells and in higher expression in HCC4006 cells ( Figure 1C).…”

Section: Resultsmentioning

confidence: 84%

“…In colon cancer, miR-218 was found to suppress invasion and migration by inhibiting ZEB2 and N-Cadherin [9]. Moreover, miR-218 upregulation was found to inhibit gastric cancer invasion by targeting Gli2 and E-cadherin following Thermo-chemotherapy [10]. These findings suggest that miR-218 is involved in the EMT process by targeting N-Cadherin and E-cadherin, which are the key molecular makers associated with EMT.…”

mentioning

confidence: 82%

miR-218 suppresses epithelial-to-mesenchymal transition by targeting Robo1 and Ecop in lung adenocarcinoma cells

Zhang

Xia

et al. 2017

Future Oncol.

View full text Add to dashboard Cite

Aim: Although, miR-218 has been implicated in epithelial-to-mesenchymal transition process, the detailed mechanisms of miR-218 involvement in epithelial-to-mesenchymal transition in human lung adenocarcinoma cell are still unclear. Materials & methods: miR-218 function assays and its target gene analysis were performed. Results: miR-218 suppresses human lung adenocarcinoma cell migration and invasion and inhibits its target gene, Ecop and Robo1 expression, which subsequently suppresses NF-κB activity and its downstream targets. Conclusion: miR-218 inhibits human lung adenocarcinoma cell migration and invasion via the suppression of Ecop and Robo1 expression, thus suggesting that miR-218 could serve as a potential therapeutic target. In tumor cells, the epithelial-to-mesenchymal transition (EMT) is an essential biological process that confers the capabilities of invasion and metastasis [1]. Once these capabilities are obtained, complete removal by surgical resection is difficult, thus leading to easy relapses and contributing to a great majority of deaths worldwide [2]. During the EMT process, cancer cells down-regulate gene expression relating to cell to cell contact, for example, Ecadherin, and upregulate the expression of mesenchymal markers, including vimentin, fibronectin and N-cadherin, thus enhancing cancer cell migration and invasion [3]. miRNAs are endogenous small noncoding RNAs that play a crucial role in gene expression regulation, with some target genes implicated in tumor cell invasion and metastasis and EMT suppression/promotion. One study found that miR-27 up-regulation increased EMT-associated gene expression to include ZEB1, ZEB2, slug and vimentin and decreased E-cadherin expression. This study also showed that miR-27 promoted human gastric cancer cell metastasis by inducing EMT [4]. Another study found that miR-214 downregulation promoted intrahepatic cholangiocarcinoma metastasis by targeting Twist, which is an important transcription factor regulating EMT, and by inhibiting E-cadherin expression and promoting N-cadherin, C-fos and MMP-9 expression, thus suggesting that miR-214 is an EMT-suppressive miRNA [5]. Furthermore, increasing evidence has shown that EMT-suppressive miRNAs have a reduced expression in human tumor tissue when compared with tumor-adjacent normal tissue, thus enabling EMT progression. Another EMT-suppressive miRNA, miR-655, when overexpressed has been shown to upregulate E-cadherin and suppress migration and invasion of mesenchymal-like cancer cells to include promoting a morphological shift toward an epithelial phenotype [6]. Furthermore, another recent study showed that the miR-200 family (miR-141, -200a, -200b, -200c and -429) and miR-205 act as EMT-suppressive miRNAs directly targeting ZEB1 and ZEB2 [7,8]. In colon cancer, miR-218 was found to suppress invasion and migration by inhibiting ZEB2 and N-Cadherin [9]. Moreover, miR-218 upregulation was found to inhibit gastric cancer invasion by targeting Gli2 and E-cadherin following Thermo-chemotherapy [10]. These findi...

show abstract

MiR-218 sensitizes glioma cells to apoptosis and inhibits tumorigenicity by regulating ECOP-mediated suppression of NF-κB activity

Abstract: These results suggest that miR-218 sensitizes glioma cells to apoptosis by regulating ECOP-mediated suppression of NF-κB activity, which may provide novel opportunities for glioma therapy.

Cited by 74 publications

References 30 publications

miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma

miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma

Increased level of H19 long noncoding RNA promotes invasion, angiogenesis, and stemness of glioblastoma cells

miR-218 suppresses epithelial-to-mesenchymal transition by targeting Robo1 and Ecop in lung adenocarcinoma cells

Contact Info

Product

Resources

About