BioProject

A growing body of literature has proposed cell-autonomous tumor suppressor functions for the mir-143~145 cluster in a variety of human cancers, including lung adenocarcinoma, and has reported therapeutic benefits of delivering mir-143 and mir- 145 to tumors. More...

A growing body of literature has proposed cell-autonomous tumor suppressor functions for the mir-143~145 cluster in a variety of human cancers, including lung adenocarcinoma, and has reported therapeutic benefits of delivering mir-143 and mir- 145 to tumors. In contrast to these studies, we found that depletion or forced expression of mir-143 and mir-145 in an autochthonous mouse model of lung adenocarcinoma did not affect tumor development. Surprisingly, we observed that loss of mir-143~145 from the tumor microenvironment significantly reduced tumor burden, indicating a non-cell- autonomous role for these miRNAs in promoting tumorigenesis. By examining the expression patterns of different cell populations isolated in vivo from tumor-bearing lungs using an integrated computational approach, we identified a role for mir-145 in stimulating the proliferation of endothelial cells by downregulating an inhibitory kinase, Camk1d, which prevents mitotic entry. As a consequence, tumors in mir-143~145- deficient animals exhibited diminished hallmarks of neo-angiogenesis, increased apoptosis and their expansion appeared limited by the tumor’s ability to co-opt the alveolar vasculature. These findings show that expression of the mir-143~145 cluster in the tumor stroma promotes rather than suppresses tumorigenesis and cautions against the use of these miRNAs as agents in cancer therapeutics. Overall design: Epcam-positive, CD31-positive, and triple-negative (Epcam-CD31-CD45-) cell populations isolated by flow cytometry from tumor-bearing lungs of K-rasG12D/+, miR-143/145-proficient and -deficient mice. Three independent mice from each genotype were used as biological replicates. Less...