title: Targeting BMP9-promoted human osteosarcoma growth by inactivation of notch signaling.
abstract: Osteosarcoma (OS) is the most common primary malignancy of bone and is usually associated with poor prognosis due to its high incidence of metastasis and chemoresistance. Molecular pathogenesis of OS is poorly understood. We previously showed that OS cells are refractory to BMP9-induced osteogenesis and respond favorably to proliferation and tumor growth. Here we investigate if Notch signaling mediates the BMP9-promoted cell proliferation and tumor growth of human osteosarcoma (OS). We find that the expression of Notch1, Notch2, Notch3, DLL1, JAG1 and JAG2 is readily detected in most of the tested OS cell lines. BMP9-promoted OS cell proliferation, migration, and cell cycle S/G2 progression are effectively inhibited by a dominant-negative mutant of Notch1 (dnNotch1) or the γ-secretase inhibitor Compound E (ComE). Furthermore, BMP9-promoted tumor growth and osteolytic lesions in vivo are significantly inhibited by dnNotch1. BMP9 up-regulates the expression of Notch1, Notch3, DLL1, and JAG1 in OS cells. Accordingly, BMP9 stimulation induces a nuclear accumulation of NICD, which is blocked by ComE. Our results demonstrate that BMP9-promoted OS proliferation and tumor growth is at least in part mediated by Notch signaling, suggesting that osteogenic BMPs may function as upstream regulators of Notch signaling in OS tumorigenesis. Thus, pharmacologic intervention of Notch signaling may be explored as a new therapeutic strategy for human OS tumors.
authors.forename: Ruidong
authors.initials: R
authors.lastname: Li
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Cui
authors.forename: Wei
authors.initials: W
authors.lastname: Shui
authors.forename: Liangjun
authors.initials: L
authors.lastname: Yin
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Ningning
authors.initials: N
authors.lastname: Wu
authors.forename: Guoxin
authors.initials: G
authors.lastname: Nan
authors.forename: Xian
authors.initials: X
authors.lastname: Chen
authors.forename: Sheng
authors.initials: S
authors.lastname: Wen
authors.forename: Fang
authors.initials: F
authors.lastname: Deng
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhang
authors.forename: Guolin
authors.initials: G
authors.lastname: Zhou
authors.forename: Zhan
authors.initials: Z
authors.lastname: Liao
authors.forename: Junhui
authors.initials: J
authors.lastname: Zhang
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Zhengjian
authors.initials: Z
authors.lastname: Yan
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Zhonglin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jixing
authors.initials: J
authors.lastname: Ye
authors.forename: Youlin
authors.initials: Y
authors.lastname: Deng
authors.forename: Hue H
authors.initials: HH
authors.lastname: Luu
authors.forename: Rex C
authors.initials: RC
authors.lastname: Haydon
authors.forename: Tong-Chuan
authors.initials: TC
authors.lastname: He
authors.affiliation: Molecular Oncology Laboratory, The University of Chicago Medical Center, 5841 South Maryland Avenue, Room J-611, Chicago, IL 60637, USA. tche@uchicago.edu.
authors.forename: Zhong-Liang
authors.initials: ZL
authors.lastname: Deng
mesh_terms: D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D055427:Growth Differentiation Factor 2 / Q000502:physiology*; D006801:Humans; D012516:Osteosarcoma / Q000473:pathology* / Q000503:physiopathology
chemical_list: D055427:Growth Differentiation Factor 2