Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development
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-1...
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American Association for Cancer Research (AACR)
2018
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| Online Access: | http://hdl.handle.net/1721.1/116563 https://orcid.org/0000-0002-9303-057X https://orcid.org/0000-0002-7799-6454 https://orcid.org/0000-0001-5785-8911 |
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| author | Dimitrova, Ivana Ljubomirova Gocheva, Vasilena Bhutkar, Arjun Resnick, Rebecca Jong, Robyn Miller, Kathryn Bendor, Jordan Jacks, Tyler E. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Dimitrova, Ivana Ljubomirova Gocheva, Vasilena Bhutkar, Arjun Resnick, Rebecca Jong, Robyn Miller, Kathryn Bendor, Jordan Jacks, Tyler E. |
| author_sort | Dimitrova, Ivana Ljubomirova |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T08:40:00Z |
| format | Article |
| id | mit-1721.1/116563 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T08:40:00Z |
| publishDate | 2018 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/1165632022-09-23T13:44:18Z Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development Dimitrova, Ivana Ljubomirova Gocheva, Vasilena Bhutkar, Arjun Resnick, Rebecca Jong, Robyn Miller, Kathryn Bendor, Jordan Jacks, Tyler E. Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Dimitrova, Ivana Ljubomirova Gocheva, Vasilena Bhutkar, Arjun Resnick, Rebecca Jong, Robyn Miller, Kathryn Bendor, Jordan Jacks, Tyler E. 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. National Institutes of Health (U.S.) (Grant P01-CA42063-26) National Cancer Institute (U.S.) (Grant P30-CA14051) 2018-06-25T15:53:48Z 2018-06-25T15:53:48Z 2015-11 2015-11 2018-06-25T15:05:23Z Article http://purl.org/eprint/type/JournalArticle 2159-8274 2159-8290 http://hdl.handle.net/1721.1/116563 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 https://orcid.org/0000-0002-9303-057X https://orcid.org/0000-0002-7799-6454 https://orcid.org/0000-0001-5785-8911 http://dx.doi.org/10.1158/2159-8290.CD-15-0854 Cancer Discovery Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research (AACR) PMC |
| spellingShingle | Dimitrova, Ivana Ljubomirova Gocheva, Vasilena Bhutkar, Arjun Resnick, Rebecca Jong, Robyn Miller, Kathryn Bendor, Jordan Jacks, Tyler E. Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development |
| title | Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development |
| title_full | Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development |
| title_fullStr | Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development |
| title_full_unstemmed | Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development |
| title_short | Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development |
| title_sort | stromal expression of mir 143 145 promotes neoangiogenesis in lung cancer development |
| url | http://hdl.handle.net/1721.1/116563 https://orcid.org/0000-0002-9303-057X https://orcid.org/0000-0002-7799-6454 https://orcid.org/0000-0001-5785-8911 |
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