HMGA1 is induced by Wnt/beta-catenin pathway and maintains cell proliferation in gastric cancer.
The development of stomach cancer is closely associated with chronic inflammation, and the Wnt/beta-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/beta-catenin pathway and maintains proliferation of gastric cancer cells. Specific knockdown of HMGA1 resulted in marked reduction of cell growth. The loss of beta-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/beta-catenin pathway. Enhanced expression of HMGA1 coexisted with the nuclear accumulation of beta-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/beta-catenin pathway.
Akaboshi
Shin-ichi
S
Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
Watanabe
Sugiko
S
Hino
Yuko
Y
Sekita
Yoko
Y
Xi
Yang
Y
Araki
Kimi
K
Yamamura
Ken-ichi
K
Oshima
Masanobu
M
Ito
Takaaki
T
Baba
Hideo
H
Nakao
Mitsuyoshi
M
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055879:Gene Knock-In Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D025741:HMGA1a Protein / Q000378:metabolism*; D006801:Humans; D053539:Keratin-19 / Q000378:metabolism; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D053539:Keratin-19; D016271:Proto-Oncogene Proteins c-myc; D051153:Wnt Proteins; D051176:beta Catenin; C485184:enhanced green fluorescent protein; D025741:HMGA1a Protein; D049452:Green Fluorescent Proteins