Original Article MicroRNA 373 and 520c Are Downregulated in Prostate Cancer, Suppress CD44 Translation, and Modulate Prostate Cancer Cell Invasion
Kui Yang, Alina M. Handorean, Kenneth A. Iczkowski
Department of Pathology, University of Colorado Health Science Center, Aurora, Colorado.
Received 06 November 2008; Accepted 08 November 2008; Available online 26 November 2008
Abstract: Prostate cancer (PCa), like most human cancers, features dysregulated CD44 expression. It loses expression of CD44 standard (CD44s), present in benign epithelium, and overexpresses a less abundant splice isoform, CD44v7-10. MicroRNAs 373 and 520c putatively regulate CD44. The levels of these two microRNAs were measured in matched benign and malignant patient tissues and in prostate cell lines. The effects of their transfection on CD44 mRNA and protein were documented. Whether these miRNAs act on CD44 promoter, or its 3' untranslated region (UTR), was studied with luciferase reporter constructs and their influences on migration and invasion were determined in PC-3M cells. miR-373 and miR-520c expression were decreased in PCa cells and tissues, in proportion to their decreases in total CD44 mRNA. Exogenous miR-373 caused a dose-dependent increase in total CD44 RNA, and decrease in CD44v7-10 RNA, with an optimal dose at 6 nM. At the protein level, however, both microRNAs suppressed CD44. Both migration and invasion were stimulated by miR-373 and miR- 520c. The microRNAs had no effect on the CD44 promoter, but did exhibit 3'UTR binding. In conclusion, miR-373 and miR-520c exert their effect in PCa by preventing the translation of CD44 RNA, rather than by degrading the RNA. Despite this observation, they exert pro-invasive functional effects, as previously described in breast cancer cells. Their effects are mediated by binding CD44 3'UTR. (IJCEP811003).
Address all correspondence to: Kenneth A. Iczkowski, M.D., Pathology—P.O. Box 6511, UCHSC—Campus Mail Stop 8104, Aurora, CO 80010. Tel: 303-724-0155, Fax: 303-724-3712, E-mail: Kenneth.Iczkowski@UCDenver.edu