Loss of mir-146a function in hormone-refractory prostate cancer
Abstract
The pattern of microRNA (miRNA) expression is associated with the degree of tumor cell differentiation in human prostate cancer. MiRNAs bind complementarily to either oncogenes or tumor suppressor genes, which are consequently silenced, resulting in alterations of tumorigenecity. We have detected eight down-regulated and three up-regulated known miRNAs in androgen-independent human prostate cancer cells compared to those in androgen-dependent cells, using miRNA microarray analyses. These identified miRNAs showed the same expression patterns in hormone-refractory prostate carcinomas (HRPC) compared to androgen-sensitive noncancerous prostate epithelium as determined by fluorescent in situ hybridization assays in human prostate cancer tissue arrays. One of the eight down-regulated miRNAs, mir-146a, was selected and constitutively expressed to examine its effects on suppression of prostate cancer transformation from androgen-dependent to -independent cells as determined by in vitro tumorigenecity assays. Transfection of mir-146a, which perpetually express the miRNA, suppressed >82% of the expression of the targeted protein-coding gene, ROCK1, in androgen-independent PC3 cells, consequently markedly reducing cell proliferation, invasion, and metastasis to human bone marrow endothelial cell monolayers. Given that ROCK1 is one of the key kinases for the activation of hyaluronan (HA)-mediated HRPC transformation in vivo and in PC3 cells, mir-146a may function as a tumor-suppressor gene in modulating HA/ROCK1-mediated tumorigenecity in androgen-dependent prostate cancer.
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Footnotes
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Reprint requests to: Shi-Lung Lin, Department of Cell and Neurobiology, Keck School of Medicine, BMT-403, University of Southern California, 1333 San Pablo Street, Los Angeles, CA 90033, USA; e-mail: lins{at}usc.edu; fax: (323) 442-3466; or Shao-Yao Ying, Department of Cell and Neurobiology, Keck School of Medicine, BMT-403, University of Southern California, 1333 San Pablo Street, Los Angeles, CA 90033, USA; e-mail: sying{at}usc.edu; fax: (323) 442-3466.
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Abbreviations: miRNA, microRNA; HRPC, hormone-refractory prostate cancer; HA, hyaluronan; CD168 (RHAMM), receptor for hyaluronan-mediated motility; ROCK, Rho-activated protein kinase; PI3K, phosphatidylinositol-(3,4,5)P3 kinase; eIF4E, cap-dependent eukaryotic initiation factor 4E; FISH, fluorescent in situ hybridization; hBMEC, human bone marrow endothelial cell.
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Article published online ahead of print. Article and publication date are at http://www.rnajournal.org/cgi/doi/10.1261/rna.874808.
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- Received October 12, 2007.
- Accepted November 14, 2007.
- Copyright © 2008 RNA Society
