title: The miR-30 Family Inhibits Pulmonary Vascular Hyperpermeability in the Premetastatic Phase by Direct Targeting of Skp2.
abstract: OBJECTIVE
  Before metastasis, primary tumor can create a premetastatic niche in distant organ to facilitate the dissemination of tumor cells. In the premetastatic phase, the permeability of pulmonary vasculatures is increased to accelerate the extravasation of circulating tumor cells. However, it is not clear whether local miRNAs contribute to the vascular hyperpermeability of the premetastatic niche.
  
  
  METHODS
  The expression of total miRNAs was determined using microarray in series of premetastatic lungs from tumor-bearing mice. Significantly differentially expressed miRNAs were identified and validated with qRT-PCR. Vascular permeability assays, vascular mimic systems, and orthotopic tumor models were used to investigate roles of selected miRNAs and target genes in premetastatic hyperpermeability.
  
  
  RESULTS
  We identified a miRNA signature in premetastatic lungs. Among these miRNAs, miR-30a, b, c, d, and e were significantly attenuated. Subsequent investigations elucidated that lung fibroblast-derived miR-30s stabilized pulmonary vessels. Overexpression of miR-30s in lungs postponed metastasis and extended overall survival of B16 tumor-bearing mice. Following studies uncovered that Skp2 was directly targeted by miR-30s. Overexpression of Skp2 could disrupt pulmonary vessels, promote lung metastasis, and decrease overall survival of B16 tumor-bearing mice.
  
  
  CONCLUSIONS
  These findings illuminate a novel mechanism for the modulation of premetastatic niches by miR-30s, which suggest that miR-30s represent not only promising targets for antimetastasis therapy but also indicators for metastasis.
authors: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Beijing, China. Beijing Key Laboratory for Protein Therapeutics, Beijing, China. Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors: Feifei
authors: F
authors: Qi
authors: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Beijing, China. Beijing Key Laboratory for Protein Therapeutics, Beijing, China. Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors: Ting
authors: T
authors: He
authors: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Beijing, China. Beijing Key Laboratory for Protein Therapeutics, Beijing, China. Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors: Lin
authors: L
authors: Jia
authors: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Beijing, China. Beijing Key Laboratory for Protein Therapeutics, Beijing, China. Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors: Nan
authors: N
authors: Song
authors: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Beijing, China. Beijing Key Laboratory for Protein Therapeutics, Beijing, China. Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors: Lifang
authors: L
authors: Guo
authors: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Beijing, China. Beijing Key Laboratory for Protein Therapeutics, Beijing, China. Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors: Xuhui
authors: X
authors: Ma
authors: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Beijing, China. Beijing Key Laboratory for Protein Therapeutics, Beijing, China. Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors: Chunying
authors: C
authors: Wang
authors: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Beijing, China. Beijing Key Laboratory for Protein Therapeutics, Beijing, China. Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors: Min
authors: M
authors: Xu
authors: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Beijing, China. Beijing Key Laboratory for Protein Therapeutics, Beijing, China. Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors: Yan
authors: Y
authors: Fu
authors: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Beijing, China. Beijing Key Laboratory for Protein Therapeutics, Beijing, China. Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors: Lin
authors: L
authors: Li
authors: National Engineering Laboratory for Anti-tumor Protein Therapeutics, Beijing, China. Beijing Key Laboratory for Protein Therapeutics, Beijing, China. Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China. yluo@tsinghua.edu.cn.
authors: Yongzhang
authors: Y
authors: Luo
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002199:Capillary Permeability; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000473:pathology; D008175:Lung Neoplasms / Q000098:blood supply* / Q000556:secondary; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009368:Neoplasm Transplantation; D034622:RNA Interference; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C534715:Mirn30d microRNA, mouse; D044786:S-Phase Kinase-Associated Proteins