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Let-7b expression determines response to chemotherapy through the regulation of Cyclin D1 in Glioblastoma

Yong Guo1, Kuipo Yan2, Jiasheng Fang1, Qiang Qu3, Ming Zhou4 and Fenghua Chen1*

Author Affiliations

1 Department of Neurosurgery, Xiangya Hospital, Central South University, 410008, Changsha, China

2 Department of Cardiology, The First Affiliated Hospital of Henan College of TCM, Zhengzhou 450008, P.R. China

3 Institute of Clinical Pharmacology, Central South University, 410008, Changsha, China

4 Cancer Institute, Central South University, 410008, Changsha, China

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Journal of Experimental & Clinical Cancer Research 2013, 32:41  doi:10.1186/1756-9966-32-41

Published: 27 June 2013

Abstract

Background

Glioblastoma is the most common type of primary brain tumors. Cisplatin is a commonly used chemotherapeutic agent for Glioblastoma patients. Despite a consistent rate of initial responses, cisplatin treatment often develops chemoresistance, leading to therapeutic failure. Cellular resistance to cisplatin is of great concern and understanding the molecular mechanisms is an utter need.

Methods

Glioblastoma cell line U251 cells were exposed to increasing doses of cisplatin for 6 months to establish cisplatin-resistant cell line U251R. The differential miRNA expression profiles in U251 and U251R cell lines were identified by microarray analysis and confirmed by Q-PCR. MiRNA mimics were transfected into U251R cells, and cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis.

Results

U251R cells showed 3.1-fold increase in cisplatin resistance compared to its parental U251 cells. Microarray analysis identified Let-7b and other miRNAs significantly down-regulated in U251R cells compared to U251 cells. Transfection of Let-7b mimics greatly re-sensitized U251R cells to cisplatin, while transfection of other miRNAs has no effect or slightly effect. Cyclin D1 is predicted as a target of Let-7b through bioinformatics analysis. Over-expression of Let-7b mimics suppressed cyclin D1 protein expression and inhibited cyclin D1-3’-UTR luciferase activity. Knockdown of cyclin D1 expression significantly increased cisplatin-induced G1 arrest and apoptosis.

Conclusions

Collectively, our results indicated that cisplatin treatment leads to Let-7b suppression, which in turn up-regulates cyclin D1 expression. Let-7b may serve as a marker of cisplatin resistance, and can enhance the therapeutic benefit of cisplatin in glioblastoma cells.

Keywords:
Glioblastoma; Let-7b; Cisplatin; Drug resistance; Cyclin D1