Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development
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Author(s)
Dimitrova, Ivana Ljubomirova
Gocheva, Vasilena
Bhutkar, Arjun
Resnick, Rebecca
Jong, Robyn
Miller, Kathryn
Bendor, Jordan
Jacks, Tyler E.
Date Issued
November 2015
Journal
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
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1158/2159-8290.CD-15-0854
