The miR-363-GATA6-Lgr5 pathway is critical for colorectal tumourigenesis

Shinnosuke Tsuji, Yoshihiro Kawasaki, Shiori Furukawa, Kenzui Taniue, Tomoatsu Hayashi, Masumi Okuno, Masaya Hiyoshi, Joji Kitayama and Tetsu Akiyama ()
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Shinnosuke Tsuji: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo
Yoshihiro Kawasaki: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo
Shiori Furukawa: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo
Kenzui Taniue: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo
Tomoatsu Hayashi: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo
Masumi Okuno: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo
Masaya Hiyoshi: Graduate school of Medicine, The University of Tokyo
Joji Kitayama: Graduate school of Medicine, The University of Tokyo
Tetsu Akiyama: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: Abstract Aberrant activation of Wnt signalling results in colorectal tumours. Lgr5 is specifically expressed in stem cells of the intestine and has an essential role in maintaining tissue homeostasis. Lgr5-positive stem cells are responsible for the intestinal adenoma initiated by mutations in adenomatous polyposis coli. Furthermore, Lgr5 interacts with R-spondins and thereby activates Wnt signalling. However, the function of Lgr5 in colorectal tumourigenesis is unclear. Here we show that LGR5 is required for the tumourigenicity of colorectal cancer cells. We show that the transcription factor GATA6 directly enhances the expression of LGR5. We further demonstrate that GATA6 is upregulated in colorectal cancer cells due to the downregulation of miR-363, which directly targets GATA6. Moreover, we show that overexpression of miR-363 suppresses the tumourigenicity of colorectal cancer cells. These results suggest that the miR-363-GATA6-LGR5 pathway is critical for colorectal tumourigenesis and would be a promising target for the treatment of colorectal cancer.

Date: 2014
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DOI: 10.1038/ncomms4150

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