Abstract
BackgroundThe mechanisms responsible for cervical cancer radioresistance are still largely unexplored. The present study aimed to identify miRNAs associated with radioresistance of cervical cancer cells.MethodsThe radioresistant cervical cancer cell variants were established by repeated selection with irradiation. The miRNA profiles of radioresistant cells and their corresponding controls were analyzed and compared using microarray. Differentially expressed miRNAs were confirmed by quantitative real-time PCR. Cervical cancer cells were transfected with miRNA-specific mimics or inhibitors. Radiosensitivity of cervical cancer cells were determined using colony-forming assay.ResultsAmong the differentially expressed miRNAs, 20 miRNAs showed the similar pattern of alteration (14 miRNAs were overexpressed whilst 6 were suppressed) in all three radioresistant cervical cancer cell variants compared to their controls. A miRNA signature consisting of 4 miRNAs (miR-630, miR-1246, miR-1290 and miR-3138) exhibited more than 5 folds of increase in radioresistant cells. Subsequent analysis revealed that these four miRNAs could be up-regulated in cervical cancer cells by radiation treatment in both time-dependent and dose-dependent manners. Ectopic expression of each of these 4 miRNAs can dramatically increase the survival fraction of irradiated cervical cancer cells. Moreover, inhibition of miR-630, one miRNA of the specific signature, could reverse radioresistance of cervical cancer cells.ConclusionsThe present study indicated that miRNA is involved in radioresistance of human cervical cancer cells and that a specific miRNA signature consisting of miR-630, miR-1246, miR-1290 and miR-3138 could promote radioresistance of cervical cancer cells.
Highlights
The mechanisms responsible for cervical cancer radioresistance are still largely unexplored
We have demonstrated that N-Myc downstream-regulated gene 2 (NDRG2) could promote radioresistance of cervical cancer Hela cells [22]
It was shown that the cell survival fractions of Hela-R11, Siha-R15 and Hela-NDRG2 cells were strikingly increased when compared to Hela, Siha and Hela-C cells as their controls respectively (Figure 1). These results indicated that Hela-R11, Siha-R15 and Hela-NDRG2 cell lines were successfully established as the radioresistant cervical cancer cell variants
Summary
The mechanisms responsible for cervical cancer radioresistance are still largely unexplored. The present study aimed to identify miRNAs associated with radioresistance of cervical cancer cells. Radiotherapy has a significant role in definitive and adjuvant therapy for cervical cancer. Investigations showed that radiotherapy is used to treat more than 60% of cervical cancer cases [2]. Studies indicated that the overall incidence of local recurrence is 13% following definitive radiotherapy [3], which suggesting that recurrence after radiotherapy remains a problem in the treatment of cervical cancer. EGFR [7,8], Cox-2 [9,10], AKT [11], and Her-2 [12] were suggested playing some roles in radioresistance in cervical cancer in different ways. Mechanisms responsible for cervical cancer radioresistance are still largely unexplored
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