MiR-93 enhances angiogenesis and metastasis by targeting LATS2

University of Toronto
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 10/2012; 11(23). DOI: 10.4161/cc.22670
Source: PubMed


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) is 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.

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    • "Finally, Fang et al. reported that miR-93, a miRNA from the miR-106B-25 cluster and a paralog of the miR-17-92 cluster, has both pro- and antiangiogenic properties. It enhanced EC activities, including cell spreading and tube formation in a human breast carcinoma cell line by targeting the LATS2 gene (large tumour suppressor kinase 2), whereas it was found to be upregulated in human breast carcinoma tissues [90]. "
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    ABSTRACT: MicroRNAs are one class of small, endogenous, non-coding RNAs that are approximately 22 nucleotides in length; they are very numerous, have been phylogenetically conserved, and involved in biological processes such as development, differentiation, cell proliferation, and apoptosis. MicroRNAs contribute to modulating the expression levels of specific proteins based on sequence complementarity with their target mRNA molecules and so they play a key role in both health and disease. Angiogenesis is the process of new blood vessel formation from preexisting ones, which is particularly relevant to cancer and its progression. Over the last few years, microRNAs have emerged as critical regulators of signalling pathways in multiple cell types including endothelial and perivascular cells. This review summarises the role of miRNAs in tumour angiogenesis and their potential implications as therapeutic targets in cancer.
    BioMed Research International 08/2014; 2014:878450. DOI:10.1155/2014/878450 · 3.17 Impact Factor
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    • "MiR-93, derived from a paralogue (miR-106b-25) of miR-17-92 cluster, is up-regulated in various types of cancers [30-32]. The identified targets of miR-93 include LATS2 [33], AICDA [34], ITGB8 [35], PTEN [36], VEGFA [37], TP53INP1 [38], DAB2 [39], etc., suggesting that miR-93 may play oncogenic roles through diverse mechanisms. However, the targetome of miR-93 in cancer has not been fully defined so far. "
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    • "Significantly, LATS2 expression levels are further regulated on the transcriptional level by the transcription factors FOXP3 and p53 [74,75]. LATS2 expression is also regulated by TTP (tristetraprolin), an ARE (AU-rich element) binding protein that promotes the degradation of ARE-containing transcripts [76], and at least six different microRNAs have been shown to negatively regulate LATS2 expression [77-81]. "
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    ABSTRACT: The metazoan Hippo pathway is an essential tumour suppressor signalling cascade that ensures normal tissue growth by co-ordinating cell proliferation, cell death and cell differentiation. Over the past years, various genetic and biochemical studies in Drosophila and mammals have defined a conserved core Hippo signalling module, composed of members of the Ste20-like kinase, the MOB co-activator and the AGC kinase families. In Drosophila, stimulated Hippo kinase phosphorylates and thereby activates the Mats/Warts complex, which consequently phosphorylates and inactivates the transcriptional co-activator Yorkie. In mammals, the counterparts of the Hippo/Mats/Warts/Yorkie cascade, namely MST1/2, MOB1A/B, LATS1/2 and YAP/TAZ, function in a similar fashion. These canonical Hippo pathways are so highly conserved that human MST2, hMOB1A and LATS1 can compensate for the loss of Hippo, Mats and Warts in flies. However, recent reports have shown that Hippo signalling is more diverse and complex, in particular in mammals. In this review, we summarize our current understanding of mammalian LATS1/2 kinases together with their closest relatives, the NDR1/2 kinases. The regulation of the LATS/NDR family of kinases will be discussed, followed by a summary of all currently known LATS/NDR substrates. Last, but not least, the biological roles of LATS/NDR kinases will be reviewed with specific emphasis on recent discoveries of canonical and non-canonical LATS/NDR functions in the extended Hippo pathway.
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