title: REG4 is a transcriptional target of GATA6 and is essential for colorectal tumorigenesis.
abstract: The transcription factor GATA6 is a critical regulator of cell proliferation and development in the gastrointestinal tract. We have recently reported that GATA6 induces the expression of the intestinal stem cell marker LGR5 and enhances the clonogenicity and tumorigenicity of colon cancer cells, but not the growth of these cells cultured under adherent conditions. Here we show that REG4, a member of the regenerating islet-derived (REG) family, is also a target of GATA6. We further demonstrate that REG4 is downregulated by overexpression of miR-363, which suppresses GATA6 expression. Moreover, we show that GATA6-mediated activation of REG4 enhances the growth of colon cancer cells under adherent conditions and is required for their tumorigenicity. Taken together, our findings demonstrate that GATA6 simultaneously induces the expression of genes essential for the growth of colon cancer cells under adherent conditions (REG4) and genes required for their clonogenicity (LGR5), and that the miR-363-GATA6-REG4/LGR5 signaling cascade promotes the tumorigenicity of colon cancer cells.
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawasaki
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Matsumura
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Miyamoto
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Shinnosuke
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Masumi
authors.initials: M
authors.lastname: Okuno
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Sakiko
authors.initials: S
authors.lastname: Suda
authors.affiliation: Department of Surgical Oncology, Graduate school of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Hiyoshi
authors.affiliation: Department of Surgical Oncology, Graduate school of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Joji
authors.initials: J
authors.lastname: Kitayama
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Akiyama
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D050993:GATA6 Transcription Factor / Q000378:metabolism*; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; C116884:LGR5 protein, human; D037181:Lectins, C-Type; C574861:MIRN363 microRNA, human; D035683:MicroRNAs; D000073718:Pancreatitis-Associated Proteins; C428528:REG4 protein, human; D043562:Receptors, G-Protein-Coupled