MiR-145 functions as a tumor-suppressive RNA by targeting Sox9 and adducin 3 in human glioma cells |
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Authors: | Sandhya B Rani Sachin Shivaji Rathod Shanmuganandam Karthik Navjot Kaur Dattatraya Muzumdar Anjali S Shiras |
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Institution: | National Centre for Cell Science, Pune, India (S.B.R., S.S.R., S.K., N.K., A.S.); Seth GS Medical College and KEM Hospital, Mumbai, India (D.M.) |
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Abstract: | BackgroundMicroRNAs (miRNAs) are increasingly being recognized as being involved in cancer development and progression in gliomas.MethodsUsing 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).ResultsInhibiting 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.ConclusionOur 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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Keywords: | adducin 3 glioma stem cells invasion neoplastic transformation promoter methylation Sox9 |
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