Blake Maresh

Introduction.  Prostate cancer is the second leading cause of mortality in adult men diagnosed with a malignancy.^1,2 Castration-resistant prostate cancer (CRPC) is currently an incurable disease in which androgen deprivation therapy (ADT) is no longer viable, indicating progression of hormone sensitive prostate cancer towards malignancy.^2,3,4 As compared to healthy controls, patients with both hormone sensitive prostate cancer as well as castration-resistant prostate cancer (CRPC), had levels of miRNA-221/222 expression that were altered. There is variable data presented in this recent field of study, with certain studies pointing to overexpression of miRNA-221/222 and others to under expression as the underlying factor in prostate cancer and its progression to the CRPC phenotype. Methods. A CRPC miRNA signature was constructed by PCR-based array methods. The association between miRNA expression and overall survival was estimated by the Kaplan-Meier method. In silico database and genome-wide gene expression analyses were performed to identify molecular targets regulated by the miR-221/222 cluster.⁵ miRNA expression profiles were also determined by miRNA microarray analysis and cell cycle analysis⁵, as well as cell proliferation assays.¹ RNA-seq was performed to identify the miRNA-221/222 transcript and RT-qPCR to determine its expression level.³ A xenograft mouse model was used to mimic clinical CRPC development and progression in order to examine gene expression changes before and after castration.³ Results. There have been contrasting studies related to miRNA-221/222 expression in prostate cancer progression. Some studies showed decreased expression levels of miRNA-221/222 in CRPC cells⁵, while others showed an increase in expression of miRNA-221/222 along with its co-transcribed long non-coding RNA (lncRNA) MIR222HG.¹ Furthermore, it was shown in another study that there was overexpression of miRNA-221/222 immediately following castration, but once the androgen receptor became overexpressed in these tumor cells there was then a suppression in the expression of miRNA-221/222.³ Conclusion. The level of expression of miRNA-221/222 in prostate cancer cells expressing the CRPC phenotype is still controversial. It is still unclear how miRNA-221/-222 are transcriptionally regulated during prostate cancer progression from androgen-dependent to castration-resistant. Recent studies indicate the possibility of overexpression followed by under expression in the development from androgen-sensitive prostate cancer to CRPC, which may help to explain the controversy in results seen between different studies. Further research is necessary in order to provide diagnostic or therapeutic targets related to miRNA-221/222 expression that could be used to improve patient care and outcomes.

1. Tong Sun, Shin-Yi Du, Joshua Armenia, et al. Expression of lncRNA MIR222HG co-transcribed from the miR-221/222 gene promoter facilitates the development of castration-resistant prostate cancer. Oncogenesis. 2018;7(3):30.
2. Jing-Wen Shih, Ling-Yu Wang, Chiu-Lien Hung, et al. Non-coding RNAs in castration-resistant prostate cancer: Regulation of androgen receptor signaling and cancer metabolism. Int Journal of Mol Sciences. 2015;16(12):28943-28978.
3. Bin Gui, Chen-Lin Hsieh, Philip W. Kantoff, et al. Androgen receptor-mediated downregulation of microRNA-221 and -222 in castration-resistant prostate cancer. PLoS One. 2017;12(9): e0184166.
4. Song ChunJiao, Chen Huan, Xu ChaoYang, Ru GuoMei. Uncovering the roles of miRNAs and their relationship with androgen receptor in prostate cancer. IUBMB Life. 2014;66(6):379-386.
5. Yusuke Goto, Satoko Kojima, Rika Nishikawa, et al. MicroRNA expression signature of castration-resistant prostate cancer: the microRNA-221/222 cluster functions as a tumour suppressor and disease progression marker. Br J Cancer. 2015;113(7):1055-1065.
6. T Sun, X Wang, HH He, et al. MiR-221 promotes the development of androgen independence in prostate cancer cells via downregulation of HECTD2 and RAB1A. Oncogene. 2014;33(21):2790-2800.
7. William Thieu, Derya Tilki, Ralph W. deVere White, Christopher P. Evans. The Role of microRNA in castration-resistant prostate cancer. Urologic Oncol: Seminars and Original Investigations. 2014;32(5):517-523.
8. Richard Ottman, Camha Nguyen, Robert Lorch, Ratna Chakrabarti. MicroRNA expressions associated with progression of prostate cancer cells to antiandrogen therapy resistance. Mol Cancer. 2014;13:1.