ブックタイトル第129回例会プログラム集 - 日本薬学会北陸支部

概要

第129回例会プログラム集 - 日本薬学会北陸支部

Suppression of intestinal cancer stemness and malignant progression by homeoproteinsCDX1 and CDX2Koji Aoki 1,2,* , Kazuya Hori 1 , Akari Nitta 1 , Ayumi Igarashi 1 , Takanori Goi 3 , AkioYamaguchi 3 , Makoto M. Taketo 4 and Manabu Sugai 51Department of Pharmacology, Faculty of Med. Sci., Univ. of Fukui2PREST, Japan Science and Technology Agency3First Department of Surgery, Faculty of Med. Sci., Univ. of Fukui4Department of Pharmacology, Graduate School of Medicine, Kyoto University5Department of Molecular Genetics, Faculty of Med. Sci., Univ. of FukuiCancer stem cells are proposed to cause metastasis and relapse. CDX1 and CDX2 areintestine-specific homeoproteins and essential for control of development anddifferentiation of intestinal epithelial cells. We have previously shown that reduced levelof CDX2 accelerates colonic adenoma formation whereas its role of CDX1 is unknown.Here we showed that inactivation of CDX1 caused intestinal tumor invasion in theApc +/D716 polyposis mice, while that of both CDX1 and CDX2 caused colonic tumorinvasion. Consistently, CDX1 and CDX2 suppressed expression of a set of genes knownas an intestinal epithelial stem-cell transcriptome including the LGR5, ASCL2 and HES1genes. Expression of CDX1 and CDX2 also reduced levels of several cancer stem cellmarkers including CD44v7-10. Consistently, they conferred increased sensitivity to thechemotherapeutic agents to colon cancer cells, whereas organoid culture stem cellsderived from Cdx2 +/? -cis Apc +/D716 Cdx1 +/? intestinal tumors showed increasedproliferation than those of Apc +/D716 . These results suggested that CDX1 and CDX2negatively regulated intestinal cancer stemness. In contrast, CDX1 and CDX2 had littleeffect on Wnt pathway activity, a primary signal that controls intestinal cancer stemness.Collectively, these results suggest that CDX1 and CDX2 cooperate to suppressintestinal cancer stemness and its malignant progression probably through regulatingexpression of cancer stem-cell transcriptome.