title: Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts. Molecular, Cellular and Developmental Biology Department, Yale University, New Haven, Connecticut.
authors.forename: Nadya
authors.initials: N
authors.lastname: Dimitrova
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Vasilena
authors.initials: V
authors.lastname: Gocheva
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Arjun
authors.initials: A
authors.lastname: Bhutkar
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Resnick
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Jong
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Miller
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Jordan
authors.initials: J
authors.lastname: Bendor
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts. tjacks@mit.edu.
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
mesh_terms: D000818:Animals; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: C543499:MIRN145a microRNA, mouse; D035683:MicroRNAs; C532884:MIRN143 microRNA, mouse; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; C517602:Camk1d protein, mouse