Patterns of
microRNA (miRNA) expression are correlated to the degrees of tumor
cell differentiation in
human prostate cancer. MiRNAs can complementarily bind to either oncogenes or tumor
suppressor genes, resulting in targeted
gene silencing and thus changes of cellular tumorigenecity. Using miRNA
microarray analysis, 8 down-regulated and 3 up-regulated known miRNAs in
androgen-independent
human prostate cancer cell lines, such as
LNCaP C4-2B and PC3, compared to those
androgen-dependent
cell lines, such as
LNCaP and PC3-AR9 were consistently detected. Fluorescent in-situ hybridization assays in
human prostate cancer tissue arrays containing sixty patients at different stages also showed the same
miRNA expression patterns in
hormone-
refractory prostate carcinomas (HRPC) compared to
androgen-sensitive non-cancerous
prostate epithelium. In-vitro tumorigenecity assays using one of the identified miRNAs, mir-146a, were performed to provide validation of its function in
prostate cancer.
Gain-of-function
transfection of mir-146a markedly suppressed its targeted ROCK1
gene expression in androgen-independent PC3 cells, consequently resulting in reduced
cancer cell proliferation, invasion and
metastasis to
human bone marrow endothelial cell monolayers. Since ROCK1 is the key
kinase for activating hyaluronan-mediated HRPC transformation
in vivo and in PC3 cells, mir-146a should function as a tumor-
suppressor gene in modulating the ROCK1-associated tumorigenecity.