Oncotarget

Research Papers:

Temozolomide resistance in glioblastoma occurs by miRNA-9-targeted PTCH1, independent of sonic hedgehog level

Jessian L. Munoz _, Vivian Rodriguez-Cruz, Shakti H. Ramkissoon, Keith L. Ligon, Steven J. Greco and Pranela Rameshwar

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Oncotarget. 2015; 6:1190-1201. https://doi.org/10.18632/oncotarget.2778

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Abstract

Jessian L. Munoz1,2, Vivian Rodriguez-Cruz3, Shakti H. Ramkissoon4, Keith L. Ligon4, Steven J. Greco1, Pranela Rameshwar1,2

1New Jersey Medical School, Rutgers, Newark, NJ, USA

2Graduate School of Biomedical Science, Rutgers School of Biomedical Health Sciences, Newark, NJ, USA

3University of Puerto Rico, Chemistry Department, Cayey, Puerto Rico

4Department of Pathology, Brigham and Women’s Hospital, Boston Children’s Hospital and Harvard Medical School, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

Correspondence to:

Pranela Rameshwar, e-mail: rameshwa@njms.rutgers.edu

Keywords: glioblastoma, MicroRNA-9, PTCH, Temozolomide, P-gp

Received: October 11, 2014     Accepted: November 19, 2014     Published: February 06, 2015

ABSTRACT

Glioblastoma Multiforme (GBM), the most common and lethal adult primary tumor of the brain, showed a link between Sonic Hedgehog (SHH) pathway in the resistance to temozolomide (TMZ). PTCH1, the SHH receptor, can tonically represses signaling by endocytosis. We asked how the decrease in PTCH1 in GBM cells could lead to TMZ-resistance. TMZ resistant GBM cells have increased PTCH1 mRNA and reduced protein. Knockdown of Dicer, a Type III RNAase, indicated that miRNAs can explain the decreased PTCH1 in TMZ resistant cells. Computational studies, real-time PCR, reporter gene studies, western blots, target protector oligos and ectopic expression identified miR-9 as the target of PTCH1 in resistant GBM cells with concomitant activation of SHH signaling. MiR-9 mediated increases in the drug efflux transporters, MDR1 and ABCG2. MiR-9 was increased in the tissues from GBM patients and in an early passage GBM cell line from a patient with recurrent GBM but not from a naïve patient. Pharmacological inhibition of SHH signaling sensitized the GBM cells to TMZ. Taken together, miR-9 targets PTCH1 in GBM cells by a SHH-independent method in GBM cells for TMZ resistance. The identified pathways could lead to new strategies to target GBM with combinations of drugs.


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