Dataset Information

Targeting oncogenic miR-335 inhibits growth and invasion of malignant astrocytoma cells.

ABSTRACT:

Background

Astrocytomas are the most common and aggressive brain tumors characterized by their highly invasive growth. Gain of chromosome 7 with a hot spot at 7q32 appears to be the most prominent aberration in astrocytoma. Previously reports have shown that microRNA-335 (miR-335) resided on chromosome 7q32 is deregulated in many cancers; however, the biological function of miR-335 in astrocytoma has yet to be elucidated.

Results

We report that miR-335 acts as a tumor promoter in conferring tumorigenic features such as growth and invasion on malignant astrocytoma. The miR-335 level is highly elevated in C6 astrocytoma cells and human malignant astrocytomas. Ectopic expression of miR-335 in C6 cells dramatically enhances cell viability, colony-forming ability and invasiveness. Conversely, delivery of antagonist specific for miR-335 (antagomir-335) to C6 cells results in growth arrest, cell apoptosis, invasion repression and marked regression of astrocytoma xenografts. Further investigation reveals that miR-335 targets disheveled-associated activator of morphogenesis 1(Daam1) at posttranscriptional level. Moreover, silencing of endogenous Daam1 (siDaam1) could mimic the oncogenic effects of miR-335 and reverse the growth arrest, proapoptotic and invasion repression effects induced by antagomir-335. Notably, the oncogenic effects of miR-335 and siDAAM1 together with anti-tumor effects of antagomir-335 are also confirmed in human astrocytoma U87-MG cells.

Conclusion

These findings suggest an oncogenic role of miR-335 and shed new lights on the therapy of malignant astrocytomas by targeting miR-335.

SUBMITTER: Shu M

PROVIDER: S-EPMC3129318 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Publications

Targeting oncogenic miR-335 inhibits growth and invasion of malignant astrocytoma cells.

Shu Minfeng M Zheng Xiaoke X Wu Sihan S Lu Huimin H Leng Tiandong T Zhu Wenbo W Zhou Yuehan Y Ou Yanqiu Y Lin Xi X Lin Yuan Y Xu Dong D Zhou Yuxi Y Yan Guangmei G

Molecular cancer 20110519

<h4>Background</h4>Astrocytomas are the most common and aggressive brain tumors characterized by their highly invasive growth. Gain of chromosome 7 with a hot spot at 7q32 appears to be the most prominent aberration in astrocytoma. Previously reports have shown that microRNA-335 (miR-335) resided on chromosome 7q32 is deregulated in many cancers; however, the biological function of miR-335 in astrocytoma has yet to be elucidated.<h4>Results</h4>We report that miR-335 acts as a tumor promoter in ...[more]

PMID: 21592405

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Project description:Astrocytomas are common malignant intracranial tumors that comprise the majority of adult primary central nervous system tumors. MicroRNAs (miRNAs) are small, non-coding RNAs (20-24 nucleotides) that post-transcriptionally modulate gene expression by negatively regulating the stability or translational efficiency of their target mRNAs. In our previous studies, we found that the downregulation of miR-106a-5p in astrocytomas is associated with poor prognosis. However, its specific gene target(s) and underlying functional mechanism(s) in astrocytomas remain unclear. In this study, we used mRNA microarray experiments to measure global mRNA expression in the presence of increased or decreased miR-106a-5p levels. We then performed bioinformatics analysis based on multiple target prediction algorithms to obtain candidate target genes that were further validated by computational predictions, western blot analysis, quantitative real-time PCR, and the luciferase reporter assay. Fas-activated serine/threonine kinase (FASTK) was identified as a direct target of miR-106a-5p. In human astrocytomas, miR-106a-5p is downregulated and negatively associated with clinical staging, whereas FASTK is upregulated and positively associated with advanced clinical stages, at both the protein and mRNA levels. Furthermore, Kaplan-Meier analysis revealed that the reduced expression of miR-106a-5p or the increased expression of FASTK is significantly associated with poor survival outcome. These results further supported the finding that FASTK is a direct target gene of miR-106a-5p. Next, we explored the function of miR-106a-5p and FASTK during astrocytoma progression. Through gain-of-function and loss-of-function studies, we demonstrated that miR-106a-5p can significantly inhibit cell proliferation and migration and can promote cell apoptosis in vitro. The knockdown of FASTK induced similar effects on astrocytoma cells as those induced by the overexpression of miR-106a-5p. These observations suggest that miR-106a-5p functions as a tumor suppressor during the development of astrocytomas by targeting FASTK.

Project description:BACKGROUND: Epithelial ovarian cancer (EOC) is still a major gynecologic problem with poor 5 year survival rate due to distance metastases, despite routine surgery and chemotherapy. The precise underlying molecular mechanisms that trigger EOC migration and invasion are unclear. Recent studies suggest that the expression of microRNAs is widely dysregulated in ovarian cancer; and that they have evolved into tumorigenic processes, including cell proliferation, apoptosis and motility. METHODS: The expression of miR-124 was assessed in clinical ovarian cancer specimens and cell lines using miRNA qRTPCR. The function of miR-124 on cell migration and invasion was confirmed in vitro through wound healing assay and transwell assay. Luciferase reporter assay was used to confirm target associations. RESULTS: We showed that miR-124 is down-regulated in ovarian cancer specimens as well as in cell lines; and that low-level expression of miR-124 is much lower in highly metastatic ovarian cancer cells and tissues. Meantime, overexpression of miR-124 dramatically inhibits the motility of ovarian cancer cells in vitro and substantially suppresses the protein expression of SphK1, reported as an invasion and metastasis-related gene in human cancers, whose expression is markedly increased in both ovarian cancer cell lines and clinical samples, particularly in two highly metastasis cells, SKOV3-ip and HO8910pm as well as metastatic ovarian tumor tissues. Furthermore, SphK1 is identified as a direct target of miR-124, and knock-down of SphK1 in ovarian cancer cells, SKOV3-ip and HO8910pm, could mimic the inhibition of migration and invasion by miR-124, while re-introduction of SphK1 abrogates the suppression of motility and invasiveness induced by miR-124 in both cell lines. CONCLUSIONS: Our studies suggest a protective role of miR-124 in inhibition of migration and invasion in the molecular etiology of ovarian cancer, and a potentially novel application of miR-124 in the regulation of migration and invasion in EOC.

Project description:This study demonstrated that miR‐335‐5p expression was reduced in HNSCC. miR‐335‐5p expression could inhibit HNSCC cell growth, metastasis, and promote cell apoptosis while it could suppress tumor growth in vivo. We identified MAP3K2 as a novel target of miR‐335‐5p and MAP3K2 overexpression partially rescued the inhibitory role of miR‐335‐5p. Hence, miR‐335‐5p might constitute a potential therapeutic target for HNSCC patients. Mounting evidence has indicated that aberrantly expressed microRNAs (miRNAs) play key roles in tumorigenesis, including in head and neck squamous cell carcinoma (HNSCC). Previous studies have shown that miR‐335‐5p can serve as a tumor suppressor or an oncogene in cancer. However, the clinical importance and biological effects of miR‐335‐5p in HNSCC have not been determined. Here, we investigated the expression pattern, functional role, and mechanisms of miR‐335‐5p in HNSCC. We showed a decreased expression of miR‐335‐5p in HNSCC samples from the TCGA and GEO databases. Consistently, we detected a downregulation of miR‐335‐5p in HNSCC cell lines and patient tissues. The expression of miR‐335‐5p was inversely correlated with advanced clinical TNM stage and lymph node metastasis in HNSCC patients. miR‐335‐5p overexpression inhibited HNSCC cell proliferation and induced apoptosis, while miR‐335‐5p inhibition had the opposite effects. miR‐335‐5p overexpression suppressed tumor growth in mice. Bioinformatic analyses and functional assays identified MAP3K2 as a target of miR‐335‐5p, and we showed that miR‐335‐5p downregulated mitogen‐activated protein kinase kinase kinase 2 (MAP3K2) expression in HNSCC cells. We found an inverse association between MAP3K2 and miR‐335‐5p expression in 38 pairs of HNSCC tissues. Furthermore, the effect of miR‐335‐5p overexpression on growth and metastasis as well as cell apoptosis in HNSCC cells could be partially rescued by MAP3K2 expression. Collectively, our data show that miR‐335‐5p inhibits the development of HNSCC by regulating MAP3K2 expression. Thus, these findings offer novel insights into a potential therapeutic strategy for HNSCC patients.

Dataset Information

Targeting oncogenic miR-335 inhibits growth and invasion of malignant astrocytoma cells.

Background

Results

Conclusion

Publications

Targeting oncogenic miR-335 inhibits growth and invasion of malignant astrocytoma cells.

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