Published online before print September 3, 2009

This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: ajpath.2009.090069v1 175/4/1675    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Akaboshi, S.-i. Articles by Nakao, M. PubMed PubMed Citation Articles by Akaboshi, S.-i. Articles by Nakao, M.

(American Journal of Pathology. 2009;175:1675-1685.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090069

HMGA1 Is Induced by Wnt/β-Catenin Pathway and Maintains Cell Proliferation in Gastric Cancer

Shin-ichi Akaboshi^*, Sugiko Watanabe^*, Yuko Hino^*, Yoko Sekita^*, Yang Xi^*, Kimi Araki, Ken-ichi Yamamura, Masanobu Oshima, Takaaki Ito^¶, Hideo Baba and Mitsuyoshi Nakao^*

From the Departments of Medical Cell Biology,^* and Developmental Genetics, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto; the Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa; and the Departments of Gastroenterological Surgery, and Pathology and Experimental Medicine,^¶ Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

The development of stomach cancer is closely associated with chronic inflammation, and the Wnt/β-catenin signaling pathway is activated in most cases of this cancer. High-mobility group A (HMGA) proteins are oncogenic chromatin factors that are primarily expressed not only in undifferentiated tissues but also in various tumors. Here we report that HMGA1 is induced by the Wnt/β-catenin pathway and maintains proliferation of gastric cancer cells. Specific knockdown of HMGA1 resulted in marked reduction of cell growth. The loss of β-catenin or its downstream c-myc decreased HMGA1 expression, whereas Wnt3a treatment increased HMGA1 and c-myc transcripts. Furthermore, Wnt3a-induced expression of HMGA1 was inhibited by c-myc knockdown, suggesting that HMGA1 is a downstream target of the Wnt/β-catenin pathway. Enhanced expression of HMGA1 coexisted with the nuclear accumulation of β-catenin in about 30% of gastric cancer tissues. To visualize the expression of HMGA1 in vivo, transgenic mice expressing endogenous HMGA1 fused to enhanced green fluorescent protein were generated and then crossed with K19-Wnt1/C2mE mice, which develop gastric tumors through activation of both the Wnt and prostaglandin E2 pathways. Expression of HMGA1-enhanced green fluorescent protein was normally detected in the forestomach, along the upper border of the glandular stomach, but its expression was also up-regulated in cancerous glandular stomach. These data suggest that HMGA1 is involved in proliferation and gastric tumor formation via the Wnt/β-catenin pathway.