Abstract | BACKGROUND: METHODS: Using a model cell system developed in our lab to study glioma progression comprising human neuroglial culture (HNGC)-1 and HNGC-2 cells, we report here that miR-145 is one of the miRNAs significantly downregulated during malignant transformation in glioblastoma multiforme (GBM). In a study using tumor samples derived from various glioma grades, we show that expression of miR-145 is decreased in a graded manner, with GBM patients showing lowest expression relative to lower-grade gliomas (P < .05) and normal brain tissues (P < .0001). Functional studies involving ectopic expression of miR-145 in glioma cells had a negative impact on cell proliferation and tumor development, as well as invasion and induced apoptosis, providing further support to the concept that inactivation of miR-145 is important for glioma disease pathogenesis. More notably, these growth-suppressive effects of miR-145 are mediated through its target proteins Sox9 and the cell adhesion-associated molecule adducin 3 (ADD3). RESULTS: Inhibiting Sox9 and ADD3 rescued effects of miR-145 loss. Interestingly, miR-145 loss in glioma cells led to overexpression of molecules involved in cell proliferation, like cyclin D1, c-myc, and N-myc, as well as enhanced expression of cell adhesion- and invasion-related molecules N-cadherin and E-cadherin, an effect which was again restored upon miR-145 overexpression in glioma cells. The miR-145 promoter was methylated at its cytosine- phosphate- guanine (CpG) islands in the glioma cell lines studied. CONCLUSION: Our study demonstrates that miR-145 has a tumor-suppressive function in glioblastoma in that it reduces proliferation, adhesion, and invasion of glioblastoma cells, apparently by suppressing the activity of oncogenic proteins Sox9 and ADD3. Reduced levels of miR-145 may lead to neoplastic transformation and malignant progression in glioma due to unregulated activity of these proteins.
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Authors | Sandhya B Rani, Sachin Shivaji Rathod, Shanmuganandam Karthik, Navjot Kaur, Dattatraya Muzumdar, Anjali S Shiras |
Journal | Neuro-oncology
(Neuro Oncol)
Vol. 15
Issue 10
Pg. 1302-16
(Oct 2013)
ISSN: 1523-5866 [Electronic] England |
PMID | 23814265
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- ADD3 protein, human
- Calmodulin-Binding Proteins
- MIRN145 microRNA, human
- MicroRNAs
- RNA, Messenger
- SOX9 Transcription Factor
- SOX9 protein, human
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Topics |
- Animals
- Apoptosis
- Blotting, Western
- Brain Neoplasms
(genetics, metabolism, pathology)
- Calmodulin-Binding Proteins
(genetics, metabolism)
- Cell Adhesion
- Cell Cycle
- Cell Movement
- Cell Proliferation
- Glioma
(genetics, metabolism, pathology)
- Humans
- Mice
- Mice, Inbred NOD
- Mice, SCID
- MicroRNAs
(genetics)
- Neoplastic Stem Cells
(metabolism, pathology)
- RNA, Messenger
(genetics)
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- SOX9 Transcription Factor
(genetics, metabolism)
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