Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development
Author(s)
Dimitrova, Ivana Ljubomirova; Gocheva, Vasilena; Bhutkar, Arjun; Resnick, Rebecca; Jong, Robyn; Miller, Kathryn; Bendor, Jordan; Jacks, Tyler E.; ... Show more Show less
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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.
Date issued
2015-11Department
Massachusetts Institute of Technology. Department of Biology; Koch Institute for Integrative Cancer Research at MITJournal
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
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
Version: Author's final manuscript
ISSN
2159-8274
2159-8290