Hath1, down-regulated in colon adenocarcinomas, inhibits proliferation and tumorigenesis of colon cancer cells.
A striking feature of colon tumors is the significant reduction of goblet cells. Although targeted deletion of Math1 in mice leads to a loss of intestinal secretory cells, including goblet cells, the role of Hath1 in colon tumorigenesis remains unknown. Here we report that Hath1, the human ortholog of Math1, was dramatically down-regulated in colon tumor samples and colon cancer cell lines. Overexpression of Hath1 in HT29, an aggressive colon cancer cell line, resulted in a significant inhibition on cell proliferation, anchorage-independent growth in soft agar and, more importantly, growth of human colon cancer cell xenografts in athymic nude mice. Such inhibition was accompanied by altered expression of a goblet cell differentiation marker, MUC2, and cell cycle regulators cyclin D1 and p27kip1. Hath1 expression also was up-regulated on inhibition of the Wnt pathway, which has been well implicated in colon tumorigenesis. Hence, this study suggests that Hath1 may be a novel factor downstream of the Wnt pathway capable of suppressing anchorage-independent growth of colon cancer cell lines. More importantly, this study is the first to establish a link between down-regulation of Hath1 expression and colon tumorigenesis.
Leow
Ching Ching
CC
Department of Molecular Oncology, Genentech, Inc., South San Francisco, California 94080, USA.
Romero
Maria S
MS
Ross
Sarajane
S
Polakis
Paul
P
Gao
Wei-Qiang
WQ
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002448:Cell Adhesion / Q000502:physiology; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D020397:Goblet Cells / Q000378:metabolism / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D055262:Mucin-2; D009077:Mucins / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction; D014162:Transfection; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics; D051153:Wnt Proteins
D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins; D055262:Mucin-2; D009077:Mucins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; C500942:ATOH1 protein, human; C500943:Atoh1 protein, mouse; C493961:Cdkn1b protein, mouse; C524625:MUC2 protein, human; C524626:Muc2 protein, mouse