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Originally published online as doi:10.2353/ajpath.2008.070346 on March 18, 2008

Published online before print March 18, 2008
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(American Journal of Pathology. 2008;172:926-939.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070346

Up-Regulation of MSX2 Enhances the Malignant Phenotype and Is Associated with Twist 1 Expression in Human Pancreatic Cancer Cells

Kennichi Satoh*, Shin Hamada*, Kenji Kimura*, Atsushi Kanno*, Morihisa Hirota*, Jun Umino*, Wataru Fujibuchi{dagger}, Atsushi Masamune*, Naoki Tanaka{ddagger}, Koh Miura{ddagger}, Shinichi Egawa{ddagger}, Fuyuhiko Motoi{ddagger}, Michiaki Unno{ddagger}, Barbara K. Vonderhaar§ and Tooru Shimosegawa*

From the Division of Gastroenterology* and the Department of Gastroenterological Surgery,{ddagger} Tohoku University Graduate School of Medicine, Sendai City, Miyagi, Japan; Advanced Industrial Science and Technology,{dagger} Koto-ku, Tokyo, Japan; and the Mammary Biology and Tumorigenesis Laboratory,§ National Cancer Institute, National Institutes of Health, Bethesda, Maryland

MSX2 is thought to be a regulator of organ development and a downstream target of the ras signaling pathway; however, little is known about the role of MSX2 in the development of pancreatic cancers, most of which harbor a K-ras gene mutation. Therefore, we examined whether the presence of MSX2 correlates with the malignant behavior of pancreatic cancer cells. BxPC3 pancreatic cancer cells that stably overexpress MSX2 showed a flattened and scattered morphology accompanied by a change in localization of E-cadherin and β-catenin from membrane to cytoplasm. Cell proliferation rate, cell migration, and anchorage-independent cell growth were enhanced in MSX2-expressing cells. Injection of MSX2-expressing cells into the pancreas of nude mice resulted in a significant increase in liver metastases and peritoneal disseminations compared with injection of control cells. Microarray analysis revealed a significant induction of Twist 1 expression in cells that express MSX2. When MSX2 was inactivated in pancreatic cancer cells following transfection with an MSX2-specific small interfering RNA, Twist 1 was down-regulated. Immunohistochemistry of human pancreatic carcinoma tissue revealed that MSX2 was frequently expressed in cancer cells, and that increased expression of MSX2 significantly correlated with higher tumor grade, vascular invasion, and Twist 1 expression. These data indicate that MSX2 plays a crucial role in pancreatic cancer development by inducing changes consistent with epithelial to mesenchymal transition through enhanced expression of Twist 1.






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