MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators

Abstract

Substantial data indicate that microRNA 21 (miR-21) is significantly elevated in glioblastoma (GBM) and in many other tumors of various origins. This microRNA has been implicated in various aspects of carcinogenesis, including cellular proliferation, apoptosis, and migration. We demonstrate that miR-21 regulates multiple genes associated with glioma cell apoptosis, migration, and invasiveness, including the RECK and TIMP3 genes, which are suppressors of malignancy and inhibitors of matrix metalloproteinases (MMPs). Specific inhibition of miR-21 with antisense oligonucleotides leads to elevated levels of RECK and TIMP3 and therefore reduces MMP activities in vitro and in a human model of gliomas in nude mice. Moreover, downregulation of miR-21 in glioma cells leads to decreases of their migratory and invasion abilities. Our data suggest that miR-21 contributes to glioma malignancy by downregulation of MMP inhibitors, which leads to activation of MMPs, thus promoting invasiveness of cancer cells. Our results also indicate that inhibition of a single oncomir, like miR-21, with specific antisense molecules can provide a novel therapeutic approach for "physiological" modulation of multiple proteins whose expression is deregulated in cancer.Malignant gliomas are brain tumors of glial origin. They are the most common type of primary brain tumors in adults and persist as serious clinical and scientific problems (reviewed in reference 40). Survival depends heavily on the histological grade of the tumor, but patients afflicted with the most malignant glioma, glioblastoma (GBM), survive on average less than 1 year. Current therapies for GBM, though they are very aggressive and usually include surgery, radiotherapy, and chemotherapy, have not been successful, due to several factors. These include rapidness and invasiveness of tumor growth, the genetic heterogeneity of the tumors, and our poor understanding of the molecular mechanisms governing disease manifestation and progression (40).MicroRNAs (miRNAs) are small regulatory RNA molecules that in recent years have been identified in the progression of various cancers and proposed as novel targets for anticancer therapies (reviewed in references 9 and 13). By negatively regulating their mRNA targets to either degradation or translational repression, they can act as both tumor suppressors and oncogenes (19,27,41,43). Using highthroughput profiling of miRNA expression, we have previously identified a specific miRNA, miRNA 21 (miR-21), as most strongly elevated in nearly all analyzed human GBM specimens (5). Other groups demonstrated overexpression of this miRNA in a wide range of other cancers, including breast, lung, colon, prostate, pancreas, ovarian, and stomach cancers, as well as in chronic lymphocytic leukemia (33, 54). These combined findings suggest miR-21 as a possible oncogene acting in a variety of cancers. miR-21 has been identified in controlling apoptosis, cell proliferation, and migration of cell lines in breast, colorectal, and other cancers (1,44,51,59).Our ai...

Hypoxia and RAS-signaling pathways converge on, and cooperatively downregulate, the RECK tumor-suppressor protein through microRNAs

“…While this study was in progress, three papers proposing RECK as a potential target of miR-21 were published (Gabriely et al, 2008;Hu et al, 2008;Zhang et al, 2008). Conversely, the links between RECK and the other two groups of miRNAs (miR-15/16 and miR-372/373) have not been described.…”

MiR‐483–5p suppresses the proliferation of glioma cells via directly targeting ERK1

“…miR-21, which is up-regulated in many solid tumors, inhibits caspase-3 dependent apoptosis in glioma cells and promotes tumor formation in vivo [4]. MiR-21 also facilitates cell invasion by directly targeting metalloprotease inhibitors TIMP3 and RECK [5]. Moreover, dysregulation of miR-21 expression is associated with chemotherapy resistance in tumor cells [6].…”

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

“…Loss of TIMP3 expression, through loss of heterozigosity on chromosome 22q, is frequently observed in various cancers, such as secondary glioblastoma (Nakamura et al, 2005) and clear renal cell carcinomas (Masson et al, 2010). Evidence is emerging that downregulation of TIMP3 expression in tumors can be achieved also through deregulation of microRNAs, as TIMP3 is a target of several microRNAs upregulated in human tumors such as miR21, miR181b, miR221 and 222 (Gabriely et al, 2008;Garofalo et al, 2009;Wang et al, 2010). The tumor-suppressor role of TIMP3 is also documented by a large body of data showing its capability to inhibit growth, invasion and metastasis of several cancers (Anand-Apte et al, 1996;Qi et al, 2003).…”