406961

MIR185

MIRN185|miR-185;microRNA 185;MIR185;microRNA 185

hsa-mir-185

22q11.21

ncRNA

Homeobox genes encode transcription factors that are essential for normal development and are often dysregulated in cancers. The molecular mechanisms that cause their misregulation in cancers are largely unknown. In this study, we investigate the mechanism by which the Six1 homeobox protein, which has a crucial role during development, is frequently deregulated in several poor outcome, aggressive, metastatic adult human cancers, including breast cancer, ovarian cancer, hepatocellular carcinoma and pediatric malignancies such as rhabdomyosarcoma and Wilms tumor. Our results reveal that miRNA-185 translationally represses Six1 by binding to its 3-untranslated region. Analyses of ovarian cancers, pediatric renal tumors and multiple breast cancer cell lines showed decreased miR-185 expression, paralleling an increase in Six1 levels. Further investigation revealed that miR-185 impedes anchorage-independent growth and cell migration, in addition to suppressing tumor growth in vivo, implicating it to be a potent tumor suppressor. Our results indicate that miR-185 mediates its tumor suppressor function by regulating cell-cycle proteins and Six1 transcriptional targets c-myc and cyclin A1. Furthermore, we show that miR-185 sensitizes Six1-overexpressing resistant cancer cells to apoptosis in general and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in particular. Together, our findings suggest that the altered expression of the novel tumor suppressor miR-185 may be one of the central events that leads to dysregulation of oncogenic protein Six1 in human cancers.

Previous studies have shown that androgen receptor (AR) is involved in the progression of prostate cancer (CaP) by several mechanisms. However, how AR is regulated has not been fully understood. In this study, miR-185 was found to be down-regulated in clinical CaP samples. Targets prediction revealed that AR had putative complementary sequences to miR-185, which was confirmed by the following dual luciferase reporter assay. Overexpression of miR-185 could reduce the expression of AR protein but not mRNA in LNCaP cells. The proliferation of LNCaP cells was inhibited by overexpression of miR-185. Cell cycle analysis revealed cell cycle arrest at G0/G1 phase. The invasive and migration abilities of cells could also be suppressed by miR-185. Furthermore, miR-185 inhibited tumorigenicity in a CaP xenografts model. CDC6, one target of AR and an important regulatory molecule for cell cycle, was found to be down-regulated by overexpression of miR-185. Our findings suggest that miR-185 could function as a tumor-suppressor gene in CaP by directly targeting AR, and act as a potential therapeutic target for CaP.