title: Twist2 functions as a tumor suppressor in murine osteosarcoma cells.
abstract: The epithelial-mesenchymal transition (EMT) contributes to the malignant progression of cancer cells including acquisition of the ability to undergo metastasis. However, whereas EMT-related transcription factors (EMT-TF) are known to play an important role in the malignant progression of epithelial tumors, their role in mesenchymal tumors remains largely unknown. We show that expression of the gene for Twist2 is downregulated in human osteosarcoma and correlates inversely with tumorigenic potential in mouse osteosarcoma. Forced expression of Twist2 in highly tumorigenic murine osteosarcoma cells induced a slight inhibition of cell growth in vitro but markedly suppressed tumor formation in vivo. Conversely, knockdown of Twist2 in osteosarcoma cells with a low tumorigenic potential promoted tumor formation in vivo, suggesting that Twist2 functions as a tumor suppressor in osteosarcoma cells. Furthermore, Twist2 induced expression of fibulin-5, which has been reported as a tumor suppressor. Medium conditioned by mouse osteosarcoma cells overexpressing Twist2 inhibited expression of the MMP9 gene as well as invasion in mouse embryonic fibroblasts, and forced expression of Twist2 in osteosarcoma cells suppressed MMP9 gene expression in tumor tissue. Data from the present study suggest that Twist2 inhibits formation of a microenvironment conducive to tumor growth and thereby attenuates tumorigenesis in osteosarcoma.
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Takatsune
authors.initials: T
authors.lastname: Shimizu
authors.forename: Arisa
authors.initials: A
authors.lastname: Ueki
authors.forename: Sayaka I
authors.initials: SI
authors.lastname: Yamaguchi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Onishi
authors.forename: Eiji
authors.initials: E
authors.lastname: Sugihara
authors.forename: Shinji
authors.initials: S
authors.lastname: Kuninaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Hideo
authors.initials: H
authors.lastname: Morioka
authors.forename: Robert
authors.initials: R
authors.lastname: Nakayama
authors.forename: Eisuke
authors.initials: E
authors.lastname: Kobayashi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Yo
authors.initials: Y
authors.lastname: Mabuchi
authors.forename: Yumi
authors.initials: Y
authors.lastname: Matsuzaki
authors.forename: Rui
authors.initials: R
authors.lastname: Yamaguchi
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D012516:Osteosarcoma / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016326:Extracellular Matrix Proteins; D012097:Repressor Proteins; D051879:Twist-Related Protein 1; C096852:Twist2 protein, mouse; D020780:Matrix Metalloproteinase 9
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