miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis

By Li Ma, Jennifer J Young, Harsha K. Prabhala, Elizabeth Pan, Pieter Mestdagh, D. Muth, J. Teruya-Feldstein, Ferenc Reinhardt, T. Onder, Scott Valastyan and 4 more. Nature Cell Biology, 2010

1,386 citations recorded by the source corpus.

MicroRNAs (miRNAs) are increasingly implicated in regulating the malignant progression of cancer. Here we show that miR-9, which is upregulated in breast cancer cells, directly targets CDH1, the E-cadherin-encoding messenger RNA, leading to increased cell motility and invasiveness. miR-9-mediated E-cadherin downregulation results in the activation of β-catenin signalling, which contributes to upregulated expression of the gene encoding vascular endothelial growth factor (VEGF); this leads, in turn, to increased tumour angiogenesis. Overexpression of miR-9 in otherwise non-metastatic breast tumour cells enables these cells to form pulmonary micrometastases in mice. Conversely, inhibiting miR-9 by using a 'miRNA sponge' in highly malignant cells inhibits metastasis formation. Expression of miR-9 is activated by MYC and MYCN, both of which directly bind to the mir-9-3 locus. Significantly, in human cancers, miR-9 levels correlate with MYCN amplification, tumour grade and metastatic status. These findings uncover a regulatory and signalling pathway involving a metastasis-promoting miRNA that is predicted to directly target expression of the key metastasis-suppressing protein E-cadherin.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9b2b3b2ae67e2e1c783065773bf2dd4b91e48012

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Citations in the corpus

MicroRNA sponges: progress and possibilities. (2010, background): “A similar approach was taken to show that miR-10b (Ma et al. 2010a) and miR-9 (Ma et al. 2010b) promote breast cancer metastasis.”
Neuroblastoma and MYCN (2013, background): “A genetically engineered mouse model of neuroblastoma (TH-MYCN) was established in 1997 and along with other studies, implicated MYCN in all aspects of tumorigenesis and malignancy (Nakagawara et al. 1994; Weiss et al. 1997; Song et al. 2007; Kang et al. 2008; Cotterman and Knoepfler 2009; Ma et al.”
MicroRNAs: New Biomarkers for Diagnosis, Prognosis, Therapy Prediction and Therapeutic Tools for Breast Cancer (2015, background): “miRNA sponges have been validated even in an SUM149-epithelial BC cell xenografted mouse model, where inhibition of Myc-driven miRNA-9 using a synthetic mRNA containing several miR-9 binding sites reduced the development of lung metastases [198].”
The ins and outs of the epithelial to mesenchymal transition in health and disease. (2011, background): “Nevertheless, some hope comes from several studies showing that systemic administration of microRNAs or aptamer-siRNA chimeras inhibit tumorigenesis and metastasis in mouse models (Dassie et al. 2009, Kota et al. 2009, Ma et al. 2010).”
Epithelial-mesenchymal plasticity in cancer progression and metastasis (2019, background): “For example, miR-9, which is upregulated in breast cancer cells, can downregulate Ecadherin expression, leading to increased cell motility and invasiveness (Ma et al., 2010).”
Non-coding RNAs in human disease (2011, background): “They act as sponges for cognate miRNAs, preventing their association with natural target”
Biological functions of microRNAs: a review (2011, background): “expression. miR-9 is up-regulated in breast cancer cells, directly targeting CDH1—the E-cadherin-encoding messenger RNA—leading to increased cell motility and invasiveness [ 31 ].”