Up-regulation of MSX2 enhances the malignant phenotype and is associated with twist 1 expression in human pancreatic cancer cells.
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 beta-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.
Satoh
Kennichi
K
Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Siryo-machi, Aobaku, Sendai City, Miyagi, Japan. ksatoh@mail.tains.tohoku.ac.jp
Hamada
Shin
S
Kimura
Kenji
K
Kanno
Atsushi
A
Hirota
Morihisa
M
Umino
Jun
J
Fujibuchi
Wataru
W
Masamune
Atsushi
A
Tanaka
Naoki
N
Miura
Koh
K
Egawa
Shinichi
S
Motoi
Fuyuhiko
F
Unno
Michiaki
M
Vonderhaar
Barbara K
BK
Shimosegawa
Tooru
T
D000328:Adult; D000368:Aged; D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D048430:Cell Shape; D004268:DNA-Binding Proteins / Q000235:genetics*; D004848:Epithelium / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010537:Peritoneum / Q000473:pathology; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C117307:KRAS protein, human; C084119:MSX2 protein; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins