Overexpression of miR-429 induces mesenchymal-to-epithelial transition (MET) in metastatic ovarian cancer cells
Research Highlights
► miR-429 induces MET in a highly metastatic ovarian cancer cell line. ► Most miR-429 induced molecular changes are indirect. ► miR-429 may be of therapeutic value in reducing OC metastasis and tumor recurrence.
Introduction
Epithelial OC is a highly metastatic disease with the highest mortality rate of all gynecologic cancers [1]. Metastasis of ovarian and other cancers is promoted by the epithelial-to-mesenchymal transition (EMT) of primary tumor cells [2], [3], [4], [5], [6]. Because metastasis is the major cause of all cancer related deaths, a number of studies have focused on the discovery of key players in the EMT with hopes of identifying potential targets for therapeutic intervention [7]. For example, the transcriptional repressor ZEB1 (zinc finger E-box binding homeobox 1) has been identified as an activator of EMT [8], [9] and knockdown of ZEB1 in undifferentiated mesenchymal-like cells has been shown to restore many features of the epithelial phenotype including elevated expression of epithelial cell markers such as the calcium-dependent adhesion protein, E-cadherin [10].
Recent studies have identified microRNAs and, more specifically, members of the miRNA-200 family of microRNAs (miR-141, miR-200a, b, c, and miR-429) and miR-205, as key players in EMT-associated cancer metastasis [11], [12], [13], [14]. ZEB1 and ZEB2 are known targets of miRNA-200 family and inhibition of these regulating microRNAs has been shown to be sufficient to induce EMT in a variety of cell types [10], [11].
Section snippets
Cell lines
The OVCAR3 cell line was originally established from the ascites of a patient with poorly differentiated papillary epithelial OC [15]. The OVCAR3 cell line was obtained from the American Type Culture Collection (Manassas, VA). The HEY cell line was derived from a patient with moderately differentiated papillary cystadenocarcinoma of the ovary [16]. The HEY cell line was kindly provided by Gordon Mills, Department of Molecular Therapeutics, University of Texas, MD Anderson Cancer Center.
microRNA transfection
6 × 104
OVCAR3 and HEY cells display molecular profiles consistent with their distinct epithelial and mesenchymal-like morphologies
To explore a possible role of microRNAs in ovarian cancer EMT and metastasis, we compared the expression levels of 2 miR-200 family microRNAs (miR-141 and miR-429), miR-205, let-7a, let-7d and miR-320 between two OC cell lines. OVCAR3 cells display a rounded/cobblestone, epithelial-like morphology while HEY cells display a more elongated morphology characteristic of mesenchymal cells (Fig. 1A) and have been shown to be significantly more invasive and metastatic than OVCAR3 cells in xenograft
Discussion
OC is a major cause of cancer death among women because it is typically not diagnosed until advanced stages of the disease when it is highly metastatic. While existing methodologies (surgery, radiation, and chemotherapy) are considered relatively effective in the treatment of primary ovarian tumors, most patients treated for advanced-staged disease will eventually suffer recurrence at metastatic sites. Since cancer metastasis is believed to be initiated by EMT, recent studies have focused on
Conflict of interest statement
The authors declare no conflict of interest.
Acknowledgments
This work was supported by grants from the Deborah Nash Harris Endowment Fund, the Robinson Family Foundation and The Ovarian Cycle Fund.
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