Targeting MicroRNAs in Prostate Cancer Radiotherapy

Abstract

Radiotherapy is one of the most important treatment options for localized early-stage or advanced-stage prostate cancer (CaP). Radioresistance (relapse after radiotherapy) is a major challenge for the current radiotherapy. There is great interest in investigating mechanisms of radioresistance and developing novel treatment strategies to overcome radioresistance. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level, participating in numerous physiological and pathological processes including cancer invasion, progression, metastasis and therapeutic resistance. Emerging evidence indicates that miRNAs play a critical role in the modulation of key cellular pathways that mediate response to radiation, influencing the radiosensitivity of the cancer cells through interplaying with other biological processes such as cell cycle checkpoints, apoptosis, autophagy, epithelial-mesenchymal transition and cancer stem cells. Here, we summarize several important miRNAs in CaP radiation response and then discuss the regulation of the major signalling pathways and biological processes by miRNAs in CaP radiotherapy. Finally, we emphasize on microRNAs as potential predictive biomarkers and/or therapeutic targets to improve CaP radiosensitivity.

Keywords: MicroRNAs; Prostate cancer; Radioresistance; Radiotherapy; Signalling pathway..

Figure 1

An overview of roles of miRNAs as a regulator of DDR in response to radiation in cancers. When SSB or DSB occurs, DNA damage repair pathway is initiated. This pathway contains a cascade of components including sensors (MRN and PAPR-1), transducers (ATM and ATR) and effectors (DNA-PK, RAD51 and BRCA1/2), in order to achieve DNA damage repair through NHEJ and HR pathways. Multiple miRNAs play important roles in up-regulating or down-regulating these biological processes in cancer radiation response. ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related protein; DNA-PK, DNA-dependent protein kinase; DSB, double-strand breaks; HR, homologous recombination; IR, irradiation; MRN, MRE11/RAD50/NBS1; NHEJ, non-homologous end joining; PARP-1, Poly [ADP-ribose] polymerase 1; SSB, single-strand breaks. '⊣' indicates down-regulation and '⟶' indicates up-regulation.

Figure 2

An overview of roles of miRNAs as a regulator of cell cycle and apoptosis in radiation response in cancers including CaP. Following the induction of DNA damage by radiation, the reaction that initiates the G1/S or G2/M cell cycle checkpoints is phosphorylation of CHK1 and CHK2 by ATM or ATR. Cell cycle progression is then interrupted to allow time for DNA damage repair by targeting the Cyclin/CDKs complexes whereby affect other components in cell cycle including CDC25, p53 and p21, in order to achieve cell cycle arrest and apoptosis. Multiple miRNAs play important roles in up-regulating or down-regulating these biological processes. CDK, cyclin-dependent kinase; CHK, checkpoint kinase; MCL1, myeloid cell leukaemia 1; SGPP1, sphingosine-1-phosphate phosphatase 1; '⊣' indicates down-regulation and '⟶' indicates up-regulation.