Prostate cancer (PCa) is an incurable disease at the metastatic stage. Although there are different options for treatment, the results are limited. MicroRNAs (miRNAs) are a group of small, noncoding, regulatory RNAs with important roles in regulating gene expression. miR-145 is reported to be a key tumor suppressor miRNA (tsmiR) that controls important oncogenes, such as MYC and RAS. In this study, in vitro studies were performed to show the control of MYC and RAS by miR-145. Flow cytometry was used to analyze cell proliferation and apoptosis. The efficacy of miR-145 in treating metastatic PCa was tested in nude mice using a model of bone metastasis promoted by intraventricular injection of PC-3MLuc-C6 cells. Tumor growth was evaluated by an in vivo bioluminescence system. After the full establishment of metastases on day 21, six animals were treated with three intravenous doses of miR-145 (on days 21, 24 and 27), and six were injected with scramble miRNA as controls. Compared to the controls, tumor growth was significantly reduced in animals receiving miR-145, most importantly on day 7 after the third and last dose of miRNA. After discontinuing the treatment, tumor growth resumed, becoming similar to the group of non-treated animals. A decrease in MYC and RAS expression was observed in all cell lines after treatment with miR-145, although statistical significance was achieved only in experiments with LNCaP and PC3 cell lines, with a decrease in 56% (p = 0.012) and 31% (p = 0.013) of RAS expression, respectively. Our results suggest that miR-145 is a potential molecule to be tested for treatment of metastatic, castration-resistant PCa.
Prostate cancer Metastasis Therapy MicroRNA Molecular biology
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We thank Mara Sa Junqueira for support with the animals. We thank Cristina Massocco Sales Gomes and Rodrigo Tannura for technical support with cell cycle assays. We thank Hernandes Faustino Carvalho for important reagents. We thank Jose Pontes Junior and Marcia Kubrusly for the critical reading of this manuscript. This study was supported by São Paulo Research Foundation (FAPESP) grants #2012/21966-8 and #2013/07350-7.
AI: Designed and performed experiments, analyzed data, performed statistical analysis and participated in writing the manuscript. STR: Designed experiments and participated in writing the manuscript. DRM: Performed experiments. NIV: Performed experiments. IAS: Performed experiments. AB: Participated in writing the manuscript. ND: Designed experiments. MS: Designed experiments, analyzed data and participated in writing the manuscript. KRML: Designed experiments, analyzed data and participated in writing the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
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