期刊
NEURO-ONCOLOGY
卷 15, 期 10, 页码 1302-1316出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/neuonc/not090
关键词
adducin 3; glioma stem cells; invasion; neoplastic transformation; promoter methylation; Sox9
资金
- Department of Biotechnology (DBT), Ministry of Science and Technology, Government of India, India
- National Centre for Cell Science (NCCS), Pune, India
- Stem Cell Task Force, Department of Biotechnology (DBT), Government of India, New Delhi, India [BT/PR10557/MED/31/29/2008]
- ICMR, New Delhi
- DBT
- Council of Scientific and Industrial Research (CSIR), New Delhi, India
Background. MicroRNAs (miRNAs) are increasingly being recognized as being involved in cancer development and progression in gliomas. 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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