MiR-93 enhances angiogenesis and metastasis by targeting LATS2

Abstract

Here we report that miR-93, a miRNA in the miR-106B~25 cluster, a paralog of the miR-17–92 cluster, was significantly upregulated in human breast carcinoma tissues. We stably expressed miR-93 in the MT-1 human breast carcinoma cell line and found that tumors formed by the miR-93 cells contained more blood vessels than those formed by the control cells. Co-culture experiments indicated that the MT-1 cells displayed a high activity of adhesion with endothelial cells and could form larger and more tube-like structures with endothelial cells. Lung metastasis assays were performed in a mouse metastatic model, and it was found that expression of miR-93 promoted tumor cell metastasis to lung tissue. In cell culture, expression of miR-93 enhanced cell survival and invasion. We examined the potential target that mediated miR-93’s effects and found that the large tumor suppressor, homology 2 (LATS2) was a target of miR-93. Higher levels of LATS2 were associated with cell death in the tumor mass. Silencing LATS2 expression promoted cell survival, tube formation and invasion, while ectopic expression of LATS2 decreased cell survival and invasion. These findings demonstrated that miR-93 promoted tumor angiogenesis and metastasis by suppressing LATS2 expression. Our results suggest that the inhibition of miR-93 function may be a feasible approach to repress tumor metastasis.

Association of microRNA-93, 190, 200b and Receptor Status in Core Biopsies from Stage III Breast Cancer Patients

“…Higher levels of this particular miRNA were found in ER-and PR-negative cohorts ( p = 0.0027 and p = 0.0185, respectively). Fang et al (2012) demonstrated higher expression of miRNA-93 in MT-1 human breast carcinoma cell lines with enhanced angiogenesis and in a lung metastasis mouse model. Furthermore, the same authors showed that higher levels of miRNA-93 were present in tumors with strong Ki-67 immunoreactivity, consistent with extensive cell proliferation.…”

“…These observations concord with our own human clinical model, because ER-and PR-negative breast cancers lead a more aggressive clinical course with greater adverse outcomes. Fang et al (2012) showed in breast cancer cell lines that the MCF-7 cells expressed significantly lower levels of miRNA-93 than MB-468 and MB-231. MCF-7 cells are characterized by positive ER and PR expression, negative HER2 amplification, and a luminal epithelial phenotype; MB-468 cells have no ER; and MB-231 cells exhibit cancer stem cell-like properties (Fang et al, 2012).…”

“…These particular miRNAs were selected on the basis of previous reports in the literature, the miRNA database, and communications from breast cancer conferences. They represent a broad range of epigenetic pathways involved in migration, invasion, receptor status, epithelialto-mesenchymal transition, cancer dormancy, switch to the fast growing phenotype, drug resistance, etc (Blenkiron et al, 2007;Lowery et al, 2008;Fang et al, 2012;Liu et al, 2012;Manavalan et al, 2013;Lehmann, 2014;Li et al, 2014;McDermott et al, 2014;www.mirbase.org). We also used unpublished data of TaqMan Low Density Arrays from our previous research.…”

“…They were first identified over a decade ago and in February 2014, a total of 2578 human miRNAs were registered in mirbase.org (www.mirbase.org). It has recently been recognized that deregulation of certain miRNAs is associated with carcinogenesis by means of oncogenes, while others act as tumor suppressors (Fang et al, 2012;Li et al, 2014;McDermott et al, 2014). It has also been speculated that certain miRNAs perform different functions in early and advanced stages of cancer (Li et al, 2014).…”

“…Breast cancerrelated genes have been extensively investigated (Ellis and Perou, 2013), but much less is known about epigenetic alterations such as microRNAs (miRNAs), DNA methylation, or histone modifications (Lehmann, 2014;Li et al, 2014;McDermott et al, 2014). MiRNAs are single-stranded, small noncoding RNAs, *18-25 nucleotides in length that potentially may modify up to one-third of the human genome (Fang et al, 2012;Li et al, 2014;McDermott et al, 2014). They were first identified over a decade ago and in February 2014, a total of 2578 human miRNAs were registered in mirbase.org (www.mirbase.org).…”