Abstract
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.
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism*
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Adenocarcinoma / pathology*
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Animals
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Basic Helix-Loop-Helix Transcription Factors
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Cell Adhesion / physiology
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Cell Cycle Proteins / biosynthesis
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Cell Cycle Proteins / genetics
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Cell Differentiation / physiology
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Cell Division / physiology
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / metabolism*
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Colorectal Neoplasms / pathology*
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Cyclin D1 / biosynthesis
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Cyclin D1 / genetics
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Cyclin-Dependent Kinase Inhibitor p27
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DNA-Binding Proteins / biosynthesis*
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DNA-Binding Proteins / genetics
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Down-Regulation
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Gene Expression Regulation, Neoplastic
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Goblet Cells / metabolism
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Goblet Cells / pathology
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HT29 Cells
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Humans
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Mice
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Mice, Nude
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Mucin-2
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Mucins / biosynthesis
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / physiology
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Signal Transduction
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Transfection
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Transplantation, Heterologous
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Tumor Suppressor Proteins / biosynthesis
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Tumor Suppressor Proteins / genetics
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Wnt Proteins
Substances
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ATOH1 protein, human
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Atoh1 protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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DNA-Binding Proteins
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MUC2 protein, human
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Muc2 protein, mouse
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Mucin-2
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Mucins
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Proto-Oncogene Proteins
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Tumor Suppressor Proteins
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Wnt Proteins
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Cyclin D1
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Cyclin-Dependent Kinase Inhibitor p27