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.

  • Source
    • "The expression of most of these miRNAs gradually increased in ESPtreated cells in a time-dependent manner. It has been reported that the expression of miR-16-2, miR-93, and miR-95 is upregulated in each case in esophageal adenocarcinoma, breast cancer, and colorectal carcinoma tissues, respectively, and that the overexpression of these molecules in the respective cells increases tumor cell proliferation and metastasis (Hu et al. 2011; Fang et al. 2012; Huang et al. 2011). In a mouse breast carcinoma cell line, miR-136 was found to target the tumor suppressor PTEN, with a consequent tumor-promoting role in cancer development (Lee et al. 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Clonorchis sinensis is a carcinogenic human liver fluke by which chronic infection is strongly associated with the development of cholangiocarcinoma. Although this cholangiocarcinoma is caused by both physical and chemical irritation from direct contact with adult worms and their excretory-secretory products (ESPs), the precise molecular events of the host-pathogen interactions remain to be elucidated. To better understand the effect of C. sinensis infection on cholangiocarcinogenesis, we profiled the kinetics of changes in cancer-related microRNAs (miRNAs) in human cholangiocarcinoma cells (HuCCT1) treated with C. sinensis ESPs for different periods. Using miRNA microarray chips containing 135 cancer-related miRNAs, we identified 16 miRNAs showing differentially altered expression following ESP exposure. Of these miRNAs, 13 were upregulated and 3 were downregulated in a time-dependent manner compared with untreated controls. Functional clustering of these dysregulated miRNAs revealed involvement in cell proliferation, inflammation, oncogene activation/suppression, migration/invasion/metastasis, and DNA methylation. In particular, decreased expression of let-7i, a tumor suppressor miRNA, was found to be associated with the ESP-induced upregulation of TLR4 mRNA and protein, which contribute to host immune responses against liver fluke infection. Further real-time quantitative PCR analysis using ESP-treated normal cholangiocytes (H69) revealed that the expressions of nine miRNAs (miR-16-2, miR-93, miR-95, miR-153, miR-195, miR-199-3P, let7a, let7i, and miR-124a) were similarly regulated, indicating that the cell proliferation and inhibition of tumor suppression mediated by these miRNAs is common to both cancerous and non-cancerous cells. These findings constitute further our understanding of the multiple cholangiocarcinogenic pathways triggered by liver fluke infection.
    Full-text · Article · Sep 2014 · Parasitology Research
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Aug 2014 · BioMed Research International
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: MiR-17-92 cluster and its paralogues have emerged as crucial regulators of many oncogenes and tumor suppressors. Transforming growth factor-beta receptor II (TGFbetaR2), as an important tumor suppressor, is involved in various cancer types. However, it is in cancer that only two miRNAs of this cluster and its paralogues have been reported so far to regulate TGFbetaR2. MiR-93 is oncogenic, but its targetome in cancer has not been fully defined. The role of miR-93 in nasopharyngeal carcinoma (NPC) still remains largely unknown. We firstly evaluated the clinical signature of TGFbetaR2 down-regulation in clinical samples, and next used a miRNA expression profiling analysis followed by multi-validations, including Luciferase reporter assay, to identify miRNAs targeting TGFbetaR2 in NPC. In vitro and in vivo studies were performed to further investigate the effects of miRNA-mediated TGFbetaR2 down-regulation on NPC aggressiveness. Finally, mechanism studies were conducted to explore the associated pathway and genes influenced by this miRNA-mediated TGFbetaR2 down-regulation. TGFbetaR2 was down-regulated in more than 50% of NPC patients. It is an unfavorable prognosis factor contributing to clinical NPC aggressiveness. A cluster set of 4 TGFbetaR2-associated miRNAs was identified; they are all from miR-17-92 cluster and its paralogues, of which miR-93 was one of the most significant miRNAs, directly targeting TGFbetaR2, promoting cell proliferation, invasion and metastasis in vitro and in vivo. Moreover, miR-93 resulted in the attenuation of Smad-dependent TGF-beta signaling and the activation of PI3K/Akt pathway by suppressing TGFbetaR2, further promoting NPC cell uncontrolled growth, invasion, metastasis and EMT-like process. Impressively, the knockdown of TGFbetaR2 by siRNA displayed a consentaneous phenocopy with the effect of miR-93 in NPC cells, supporting TGFbetaR2 is a major target of miR-93. Our findings were also substantiated by investigation of the clinical signatures of miR-93 and TGFbetaR2 in NPC. The present study reports an involvement of miR-93-mediated TGFbetaR2 down-regulation in NPC aggressiveness, thus giving extended insights into molecular mechanisms underlying cancer aggressiveness. Approaches aimed at blocking miR-93 may serve as a promising therapeutic strategy for treating NPC patients.
    Full-text · Article · Mar 2014 · Molecular Cancer
Show more