MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers

Abstract

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 0 -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 apoptosisinducing 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.

Transgenic Expression of MicroRNA-185 Causes a Developmental Arrest of T Cells by Targeting Multiple Genes Including Mzb1

“…In fact, Mcm10, Hmga1, Igf1r, and Dusp4 were additional targets. miR-185 can target Six1, RhoA, and Cdc42, genes involved in controlling cell cycle progression in various cancer cells (32)(33)(34). Interestingly, although these were not identified in our thymocyte screen, they may play a role in the peripheral Fluo-3 AM-loaded thymocytes were treated with biotinylated (Bio) anti-CD3⑀ and anti-CD4 followed by streptavidin (SA), ionomycin (Iono), and MnCl 2 .…”

MicroRNA-185 suppresses growth and invasion of colon cancer cells through inhibition of the hypoxia-inducible factor-2α pathway in vitro and in vivo

“…miR-185 was found to suppress glioma cell invasion, indicating that it may be a potential prognostic marker and therapeutic target (16). Previous studies have revealed that miR-185 impedes anchorage-independent growth, cell migration and invasion, in addition to suppressing tumor growth in vivo and increasing cisplatin sensitivity by promoting apoptosis, implicating it as a potent tumor suppressor (17)(18)(19). In the present study, overexpression of miR-185 repressed the growth and invasion of colon cancer cells in vitro and in vivo, which was consistent with the results of previous studies, indicating that miR-185 is a negative regulator of RhoA and Cdc42 and their cellular activities, and can inhibit the proliferation and invasion of CRC cells (20).…”

miR-185 and miR-133b deregulation is associated with overall survival and metastasis in colorectal cancer

“…The role of PTPN13 in colorectal cancer progression and its regulation by miR-185 need further investigations. In contrast to its oncogenic role, miR-185 has also been demonstrated to suppress tumor growth and progression in non-small lung cancer (34), ovarian, pediatric renal and breast cancer cell lines (35). These findings suggest that miR-185 may target different genes in different cell types, which contributes to different biological processes.…”