REG4 is a transcriptional target of GATA6 and is essential for colorectal tumorigenesis.
REG4 is a transcriptional target of GATA6 and is essential for colorectal tumorigenesis.
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DOI：
10.1038/srep14291
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发表时间：
2015-09-21
影响因子：
4.6
通讯作者：
Akiyama T
中科院分区：
文献类型：
--
作者：
Kawasaki Y;Matsumura K;Miyamoto M;Tsuji S;Okuno M;Suda S;Hiyoshi M;Kitayama J;Akiyama T
转录因子GATA6是胃肠道细胞增殖和发育的关键调节因子。我们最近报道GATA6诱导肠干细胞标记物LGR5的表达，增强结肠癌细胞的克隆性和致瘤性，但不增强这些细胞在贴壁条件下的生长。我们发现再生胰岛衍生（REG）家族的成员REG4也是GATA6的靶标。我们进一步证明REG4通过过表达miR-363而下调，从而抑制GATA6的表达。此外，我们发现gata6介导的REG4激活在贴壁条件下增强结肠癌细胞的生长，并且是其致瘤性所必需的。综上所述，我们的研究结果表明，GATA6同时诱导结肠癌细胞在贴壁条件下生长所需基因（REG4）和克隆性所需基因（LGR5）的表达，miR-363-GATA6-REG4/LGR5信号级联促进结肠癌细胞的致瘤性。
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.