miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis
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-...
| Main Authors: | , , , , , , , , , , , , , |
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Springer Nature
2018
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| Online Access: | http://hdl.handle.net/1721.1/116977 https://orcid.org/0000-0002-0895-3557 |
| _version_ | 1826197697016627200 |
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| author | Prabhala, Harsha Mestdagh, Pieter Muth, Daniel Teruya-Feldstein, Julie Westermann, Frank Speleman, Frank Vandesompele, Jo Ma, Li-Jun Young, Jennifer J Pan, Elizabeth Reinhardt, Ferenc Onder, Tamer T Valastyan, Scott John Weinberg, Robert A |
| author2 | Broad Institute of MIT and Harvard |
| author_facet | Broad Institute of MIT and Harvard Prabhala, Harsha Mestdagh, Pieter Muth, Daniel Teruya-Feldstein, Julie Westermann, Frank Speleman, Frank Vandesompele, Jo Ma, Li-Jun Young, Jennifer J Pan, Elizabeth Reinhardt, Ferenc Onder, Tamer T Valastyan, Scott John Weinberg, Robert A |
| author_sort | Prabhala, Harsha |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T10:51:45Z |
| format | Article |
| id | mit-1721.1/116977 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T10:51:45Z |
| publishDate | 2018 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | mit-1721.1/1169772022-09-30T23:33:32Z miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis Prabhala, Harsha Mestdagh, Pieter Muth, Daniel Teruya-Feldstein, Julie Westermann, Frank Speleman, Frank Vandesompele, Jo Ma, Li-Jun Young, Jennifer J Pan, Elizabeth Reinhardt, Ferenc Onder, Tamer T Valastyan, Scott John Weinberg, Robert A Broad Institute of MIT and Harvard Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Division of Comparative Medicine Ma, Li-Jun Young, Jennifer J Pan, Elizabeth Reinhardt, Ferenc Onder, Tamer T Valastyan, Scott John Weinberg, Robert A 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. Life Sciences Research Foundation Fellowship Margaret and Herman Sokol Award National Institutes of Health (U.S.) (Pathway to Independence Award (K99/R00)) Howard Hughes Medical Institute (Undergraduate Fellowship) Breast Cancer Research Program (U.S.) (Predoctoral Fellowship) National Institutes of Health (U.S.) (Grant) Ludwig Center for Molecular Oncology at MIT 2018-07-13T15:58:12Z 2018-07-13T15:58:12Z 2010-02 2018-07-12T18:23:41Z Article http://purl.org/eprint/type/JournalArticle 1465-7392 1476-4679 http://hdl.handle.net/1721.1/116977 Ma, Li, Jennifer Young, Harsha Prabhala, Elizabeth Pan, Pieter Mestdagh, Daniel Muth, Julie Teruya-Feldstein, et al. “miR-9, a MYC/MYCN-Activated microRNA, Regulates E-Cadherin and Cancer Metastasis.” Nature Cell Biology (February 21, 2010). https://orcid.org/0000-0002-0895-3557 http://dx.doi.org/10.1038/ncb2024 Nature Cell Biology Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Springer Nature PMC |
| spellingShingle | Prabhala, Harsha Mestdagh, Pieter Muth, Daniel Teruya-Feldstein, Julie Westermann, Frank Speleman, Frank Vandesompele, Jo Ma, Li-Jun Young, Jennifer J Pan, Elizabeth Reinhardt, Ferenc Onder, Tamer T Valastyan, Scott John Weinberg, Robert A miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis |
| title | miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis |
| title_full | miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis |
| title_fullStr | miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis |
| title_full_unstemmed | miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis |
| title_short | miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis |
| title_sort | mir 9 a myc mycn activated microrna regulates e cadherin and cancer metastasis |
| url | http://hdl.handle.net/1721.1/116977 https://orcid.org/0000-0002-0895-3557 |
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