MiR-145 functions as a tumor-suppressive RNA by targeting Sox9 and adducin 3 in human glioma cells.

Abstract

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.

• 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)

Chemical References

• ADD3 protein, human
• Calmodulin-Binding Proteins
• MIRN145 microRNA, human
• MicroRNAs
• RNA, Messenger
• SOX9 Transcription Factor
• SOX9 protein, human

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)