Hypoxia and RAS-signaling pathways converge on, and cooperatively downregulate, the RECK tumor-suppressor protein through microRNAs.
Cancer cells show characteristic gene expression profiles. Recent studies support the potential importance of microRNA (miRNA) expression signatures as biomarkers and therapeutic targets. The membrane-anchored protease regulator RECK is downregulated in many cancers, and forced expression of RECK in tumor cells results in decreased malignancy in animal models. RECK is also essential for mammalian development. In this study, we found that RECK is a target of at least three groups of miRNAs (miR-15b/16, miR-21 and miR-372/373); that RECK mutants lacking the target sites for these miRNA show augmented tumor/metastasis-suppressor activities; and that miR-372/373 are upregulated in response to hypoxia through HIF1alpha and TWIST1, whereas miR-21 is upregulated by RAS/ERK signaling. These data indicate that the hypoxia- and RAS-signaling pathways converge on RECK through miRNAs, cooperatively downregulating this tumor suppressor and thereby promoting malignant cell behavior.
Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
F
F
Loayza-Puch
Y
Y
Yoshida
T
T
Matsuzaki
C
C
Takahashi
H
H
Kitayama
M
M
Noda
D000818:Animals; D015687:Cell Hypoxia; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors*; D051879:Twist-Related Protein 1 / Q000502:physiology; D018631:ras Proteins / Q000502:physiology*
D058851:GPI-Linked Proteins; C524940:MIRN21 microRNA, human; C527114:MIRN373 microRNA, human; D008562:Membrane Glycoproteins; D035683:MicroRNAs; D009687:Nuclear Proteins; C115460:RECK protein, human; C103173:TWIST1 protein, human; D025521:Tumor Suppressor Proteins; D051879:Twist-Related Protein 1; D019859:Proto-Oncogene Proteins c-met; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins