MicroRNA-30c-2* Expressed in Ovarian Cancer Cells Suppresses Growth Factor–Induced Cellular Proliferation and Downregulates the Oncogene BCL9

Abstract

MicroRNAs (miRNAs) are small noncoding RNAs that function as master regulators of posttranscriptional gene expression with each miRNA negatively regulating hundreds of genes. Lysophosphatidic acid (LPA) is a mitogenic lipid present within the ovarian tumor microenvironment and induces LPA receptor activation and intracellular signaling cascades like ERK/MAPK, leading to enhanced cellular proliferation. Here, we show that in SKOV-3 and OVCAR-3 cells, LPA stimulation at concentrations ranging from 1 nmol/L to 20 mmol/L for 30 to 60 minutes increases miR-30c-2 Ã , and this effect is mediated through a combination of receptors because knock down of multiple LPA receptors is required for inhibition. The epidermal growth factor and platelet-derived growth factor also increase miR-30c-2 Ã transcript expression, suggesting a broader responsive role for miR-30c-2 Ã . Thus, we investigated the functional role of miR-30c-2 Ã through ectopic expression of synthetic miRNA precursors of mature miRNA or antagomir transfection and observed that microRNA-30c-2 Ã reduces, and the antagomir enhances, cell proliferation and viability in OVCAR-3, cisplatin-insensitive SKOV-3 and chemoresistant HeyA8-MDR cells. Ectopic expression of miR-30c-2 Ã reduces BCL9 mRNA transcript abundance and BCL9 protein. Consistent with this observation, miR-30c-2 Ã ectopic expression also reduced BCL9 luciferase reporter gene expression. In comparison with IOSE cells, all cancer cells examined showed increased BCL9 expression, which is consistent with its role in tumor progression. Taken together, this suggest that growth factor induced proliferation mediates a neutralizing response by significantly increasing miR-30c-2 Ã which reduces BCL9 expression and cell proliferation in SKOV-3 and OVCAR-3 cells, likely as a mechanism to regulate signal transduction downstream. Mol Cancer Res; 9(12); 1732-45. Ó2011 AACR.

miR200c Attenuates P-gp–Mediated MDR and Metastasis by Targeting JNK2/c-Jun Signaling Pathway in Colorectal Cancer

“…Recently, miRNAs, a class of noncoding RNA, were found to play important roles in various fundamental biologic processes, such as cell proliferation, apoptosis, and differentiation (12,13,14). Functioning as regulatory molecules, miRNAs are able to modulate gene expression by inhibiting the protein translation process and/or degrading the respective target messenger RNA (15).…”

Hypoxia‐induced downregulation of miR‐30c promotes epithelial‐mesenchymal transition in human renal cell carcinoma

“…For instance, miR-30c negatively regulates MTA1 in endometrial cancer cells and downregulates the oncogene BCL9 in ovarian cancer cells. (20) Twinfilin 1 and vimentin involved in tumor invasion are the targets of miR-30c in human breast cancer cells.(21) Breast cancer cell growth was suppressed by miR-30c through inhibition of KRAS expression and KRAS signaling. (22) miR-30c targets DLL4 and regulates Notch signaling to modulate endothelial cell behavior during angiogenesis.…”

“…For instance, miR-30c negatively regulates MTA1 in endometrial cancer cells and downregulates the oncogene BCL9 in ovarian cancer cells. (20) Twinfilin 1 and vimentin involved in tumor invasion are the targets of miR-30c in human breast cancer cells.…”

MicroRNAs in Ovarian Cancer

“…The demonstrated association between miRNA and their targets has most frequently been negative [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55], as summarized in Table 2. Notably, the association between miRNAs and their targets is not always straightforward, which is demonstrated by the little overlap between predicted and experimentally shown targets [56].…”