PDF(Pubmed)
Abstract：
UNASSIGNED: The demethylating agent decitabine (DAC) effectively inhibits tumor growth and metastasis by targeting ESR1 methylation to restore estrogen receptor alpha (ERα) signaling and promoting cellular differentiation in models of human osteosarcoma (OSA). Whether this pathway can be targeted in canine OSA patients is unknown.
UNASSIGNED: Canine OSA tumor samples were tested for ERα expression and ESR1 promoter methylation. Human (MG63.3) and canine (MC-KOS) OSA cell lines and murine xenografts were treated with DAC in vitro and in vivo, respectively. Samples were assessed using mRNA sequencing and tissue immunohistochemistry.
UNASSIGNED: ESR1 is methylated in a subset of canine OSA patient samples and the MC-KOS cell line. DAC treatment led to enhanced differentiation as demonstrated by increased ALPL expression, and suppressed tumor growth in vitro and in vivo. Metastatic progression was inhibited, particularly in the MG63.3 model, which expresses higher levels of DNA methyltransferases DNMT1 and 3B. DAC treatment induced significant alterations in immune response and cell cycle pathways.
UNASSIGNED: DAC treatment activates ERα signaling, promotes bone differentiation, and inhibits tumor growth and metastasis in human and canine OSA. Additional DAC-altered pathways and species- or individual-specific differences in DNMT expression may also play a role in DAC treatment of OSA.
UNASSIGNED: Canine OSA tumor samples were tested for ERα expression and ESR1 promoter methylation. Human (MG63.3) and canine (MC-KOS) OSA cell lines and murine xenografts were treated with DAC in vitro and in vivo, respectively. Samples were assessed using mRNA sequencing and tissue immunohistochemistry.
UNASSIGNED: ESR1 is methylated in a subset of canine OSA patient samples and the MC-KOS cell line. DAC treatment led to enhanced differentiation as demonstrated by increased ALPL expression, and suppressed tumor growth in vitro and in vivo. Metastatic progression was inhibited, particularly in the MG63.3 model, which expresses higher levels of DNA methyltransferases DNMT1 and 3B. DAC treatment induced significant alterations in immune response and cell cycle pathways.
UNASSIGNED: DAC treatment activates ERα signaling, promotes bone differentiation, and inhibits tumor growth and metastasis in human and canine OSA. Additional DAC-altered pathways and species- or individual-specific differences in DNMT expression may also play a role in DAC treatment of OSA.
摘要：
背景技术去甲基化剂地西他滨(DAC)通过靶向ESR1甲基化以恢复人骨肉瘤(OSA)模型中的雌激素受体α(ERα)信号传导和促进细胞分化来有效抑制肿瘤生长和转移。该途径是否可以在犬OSA患者中被靶向是未知的。方法检测犬OSA肿瘤样品的ERα表达和ESR1启动子甲基化。在体外和体内用DAC处理人（MG63.3）和犬（MC-KOS）OSA细胞系和鼠异种移植物，分别。使用mRNA测序和组织免疫组织化学评估样品。结果ESRl在犬OSA患者样品和MC-KOS细胞系的亚组中甲基化。DAC处理导致分化增强，如ALPL表达增加所证明的。并在体外和体内抑制肿瘤生长。转移进展受到抑制，特别是在MG63.3模型中，其表达较高水平的DNA甲基转移酶DNMT1和3B。DAC处理诱导免疫应答和细胞周期途径的显著改变。结论DAC治疗激活ERα信号,促进骨分化，并抑制人和犬OSA的肿瘤生长和转移。其他DAC改变的途径和DNMT表达的物种或个体特异性差异也可能在DAC治疗OSA中起作用。
