Abstract
Radiation therapy is a major primary treatment option for both localized early stage prostate cancer, and for advanced, regionally un-resectable, cancer. However, around 30% of patients still experience biochemical recurrence after radiation therapy within 10 years. Thus, identification of better biomarkers and new targets are urgently required to improve current therapeutic strategies. The miR-99 family has been shown to play an important role in the regulation of the DNA damage response, via targeting of the SWI/SNF chromatin remodeling factors, SMARCA5 and SMARCD1 in cell line models. In the present study, we have demonstrated that low expression of miR-99a and miR-100 is present in cell populations which are relatively radiation insensitive, for example in prostate cancer stem cells and in castration-resistant prostate cancer. Additionally, treatment of cells with the synthetic glucocorticoid, Dexamethasone resulted in decreased miR-99a and 100 expression, suggesting a new mechanism of miR-99a and 100 regulation in androgen-independent prostate cells. Strikingly, treatment of prostate cells with the glucocorticoid receptor inhibitor, Mifepristone was found to sensitize prostate cells to radiation by increasing the levels of miR-99a and miR-100. These results qualify the miR99 family as markers of radiation sensitivity and as potential therapeutic targets to improve efficiency of radiotherapy.
Highlights
Radiation therapy (RT) is a major primary treatment option for localized early stage prostate cancer (PCa) and regionally un-resectable advanced PCa [1, 2]
Analysis of our published miRNA expression array data demonstrates that the miR-99 family members, miR-99a and miR-100, are significantly suppressed in prostate stem-like cells (SC) compared to their differentiated progeny; committed basal (CB) cells (Figure 1A, 1B) [24, 25]
This was true for SCs and CBs enriched from benign prostatic hyperplasia (BPH), treatment naïve PCa, and castration-resistant PCa (CRPC) samples
Summary
Radiation therapy (RT) is a major primary treatment option for localized early stage prostate cancer (PCa) and regionally un-resectable advanced PCa [1, 2]. One of the main causes of the varied response to RT is the high inter- and intra-tumoral heterogeneity found in PCa [5, 6] This heterogeneity is primarily responsible for the current lack of markers to group patients into high- and low-risk for relapse, which results in overtreatment of 20–42% of patients [7]. In PCa, cell populations with the CD44+/α2β1integrinhi/CD133+, CD49fhi/Trop2hi, and CD44+/CD49fhi/Trop2+ phenotype have been shown to share CSC properties [10,11,12,13,14]. These markers have not been used to stratify patients on the basis of their radiosensitivity
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