dc.contributor.author | Dimitrova, Ivana Ljubomirova | |
dc.contributor.author | Gocheva, Vasilena | |
dc.contributor.author | Bhutkar, Arjun | |
dc.contributor.author | Resnick, Rebecca | |
dc.contributor.author | Jong, Robyn | |
dc.contributor.author | Miller, Kathryn | |
dc.contributor.author | Bendor, Jordan | |
dc.contributor.author | Jacks, Tyler E. | |
dc.date.accessioned | 2018-06-25T15:53:48Z | |
dc.date.available | 2018-06-25T15:53:48Z | |
dc.date.issued | 2015-11 | |
dc.date.submitted | 2015-11 | |
dc.identifier.issn | 2159-8274 | |
dc.identifier.issn | 2159-8290 | |
dc.identifier.uri | http://hdl.handle.net/1721.1/116563 | |
dc.description.abstract | The two unrelated miRNAs miR-143 and miR-145, coexpressed from the miR-143/145 cluster, have been proposed to act as tumor suppressors in human cancer, and therapeutic benefits of delivering miR-143 and miR-145 to tumors have been reported. In contrast, we found that tumor-specific deletion of miR-143/145 in an autochthonous mouse model of lung adenocarcinoma did not affect tumor development. This was consistent with the lack of endogenous miR-143/145 expression in normal and transformed lung epithelium. Surprisingly, miR-143/145 in the tumor microenvironment dramatically promoted tumor growth by stimulating the proliferation of endothelial cells. Loss of miR-143/145 in vivo led to derepression of the miR-145 target CAMK1D, an inhibitory kinase, which when overexpressed prevents mitotic entry of endothelial cells. As a consequence, tumors in miR-143/145-deficient animals exhibited diminished neoangiogenesis, increased apoptosis, and their expansion was limited by the tumor’s ability to co-opt the alveolar vasculature. These findings demonstrate that stromal miR-143/145 promotes tumorigenesis and caution against the use of these miRNAs as agents in cancer therapeutics.SIGNIFICANCE: This study shows that miR-143/145 expressed from the tumor microenvironment stimulates neoangiogenesis and supports tumor expansion in the lung, demonstrating a surprising role for the putative tumor suppressor miRNA cluster in promoting tumorigenesis. We propose inhibition of miR-143/145 as a therapeutic avenue to modulate tumor neoangiogenesis. | en_US |
dc.description.sponsorship | National Institutes of Health (U.S.) (Grant P01-CA42063-26) | en_US |
dc.description.sponsorship | National Cancer Institute (U.S.) (Grant P30-CA14051) | en_US |
dc.publisher | American Association for Cancer Research (AACR) | en_US |
dc.relation.isversionof | http://dx.doi.org/10.1158/2159-8290.CD-15-0854 | en_US |
dc.rights | Creative Commons Attribution-Noncommercial-Share Alike | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | en_US |
dc.source | PMC | en_US |
dc.title | Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development | en_US |
dc.type | Article | en_US |
dc.identifier.citation | Dimitrova, N. et al. “Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development.” Cancer Discovery 6, 2 (November 2015): 188–201 © 2015 American Association for Cancer Research | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Biology | en_US |
dc.contributor.department | Koch Institute for Integrative Cancer Research at MIT | en_US |
dc.contributor.mitauthor | Dimitrova, Ivana Ljubomirova | |
dc.contributor.mitauthor | Gocheva, Vasilena | |
dc.contributor.mitauthor | Bhutkar, Arjun | |
dc.contributor.mitauthor | Resnick, Rebecca | |
dc.contributor.mitauthor | Jong, Robyn | |
dc.contributor.mitauthor | Miller, Kathryn | |
dc.contributor.mitauthor | Bendor, Jordan | |
dc.contributor.mitauthor | Jacks, Tyler E. | |
dc.relation.journal | Cancer Discovery | en_US |
dc.eprint.version | Author's final manuscript | en_US |
dc.type.uri | http://purl.org/eprint/type/JournalArticle | en_US |
eprint.status | http://purl.org/eprint/status/PeerReviewed | en_US |
dc.date.updated | 2018-06-25T15:05:23Z | |
dspace.orderedauthors | Dimitrova, N.; Gocheva, V.; Bhutkar, A.; Resnick, R.; Jong, R. M.; Miller, K. M.; Bendor, J.; Jacks, T. | en_US |
dspace.embargo.terms | N | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-9303-057X | |
dc.identifier.orcid | https://orcid.org/0000-0002-7799-6454 | |
dc.identifier.orcid | https://orcid.org/0000-0001-5785-8911 | |
dspace.mitauthor.error | true | |
mit.license | OPEN_ACCESS_POLICY | en_US |