The role of microRNA-194 and microRNA-375 in prostate cancer metastasis

Abstract

Prostate cancer (PCa) is a major public health problem worldwide. In Australia, it is the most common non-dermatological cancer and second leading cause of cancer related death in men. The risk of being diagnosed with PCa increases with age, and 1 in 6 men are estimated to be affected in their lifetime. Given that Australia has an ageing population, it is projected that the number of men living with PCa will increase from 120,000 to 267,000 by 2017. While significant advances have been made in the treatment of localised, organ-confined prostate tumours, the disease becomes incurable once it has metastasized. Thus, identifying mechanisms that contribute to PCa spread is an urgent requirement. A considerable body of research has demonstrated that aberrant expression of microRNAs (miRs), a class of small non-coding regulatory RNAs, can be an important factor in prostate cancer metastasis. Previous studies in our laboratory identified serum miR-194 and miR-375 as novel markers of disease progression in men with PCa. However, whether these two miRNAs play a direct role in the biology of prostate tumors is unknown. My PhD aimed to assess the role of miR-194 and miR-375 in PCa progression and metastasis. My work demonstrated that miR-194 enhanced pro-metastatic features of PCa cells, including migration, invasion and epithelial mesenchymal transition (EMT), in vitro and also augmented metastasis in vivo. I identified and validated SOCS2 as a novel, direct and biologically relevant target of miR-194. My research supports a model whereby targeting of SOCS2 by miR-194 leads to activation of the JAK2/STAT3 and ERK1/2 signalling pathways, two key pathways involved in promoting PCa metastasis. Further, I have demonstrated that miR-194 is regulated by GATA2, an oncogenic transcription factor in PCa. On the other hand, my work demonstrated that miR-375 is a potent tumour suppressor miRNA, as it can inhibit EMT, invasion and growth of prostate cancer cells. I identified YAP1, a transcriptional coactivator and a potent oncogene, as a direct and biological relevant target of miR-375. Additionally, I demonstrated that miR-375 was under the direct transcriptional control of EMT-promoting factor, ZEB1. Collectively, these findings provide greater understanding of the role of miR-194 and miR-375 in prostate cancer metastasis. This information could inform the potential application of these miRNAs as biomarkers, and could lead to efforts to target miR-194 to prevent prostate cancer metastasis.