Department of Musculoskeletal Oncology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Eur Rev Med Pharmacol Sci. 2017 Oct;21(20):4516-4528.
To investigate the role of SATB2 in stem cell-like properties of osteosarcoma and identify new strategies to eliminate cancer stem cells of osteosarcoma.
Osteosarcoma cancer stem cells were derived by sarcosphere generation or chemo drug enrichment. SATB2 and pluripotency-associated gene expression in osteosarcoma CSCs were analyzed using qRT-PCR and Western blotting. The sphere formation assay, cell counting kit-8 assay and anti-chemotherapy proteins were used to measure the effects of altered SATB2, N-cadherin expression or metformin treatment in CSCs. Nude mice were injected with SATB2-deficient U2OS/MTX cells to assess the role of SATB2 in osteosarcoma growth and chemoresistance in vivo. Bioinformatics analyses were performed to identify SATB2 downstream target genes and immunochemistry to determine the correlation between SATB2 expression and patient outcome. Western blotting and luciferase reporter assays were used to examine the effects of N-cadherin and SATB2 inhibition on the NF-kB pathway.
SATB2 was upregulated in osteosarcoma stem cells. Knockdown of SATB2 decreased sarcosphere formation, cell proliferation and stem cell-like gene expression in vitro, meanwhile reduced tumor growth and chemoresistance in vivo. High SATB2 expression in osteosarcoma patient samples was associated with poor clinical outcome. N-cadherin was one critical downstream target gene of SATB2 that mediated the stem cell-like phenotype. Reduction of SATB2 or N-cadherin resulted in NF-kB inactivation, which led to impaired osteosarcoma sphere formation and tumor cell proliferation. Metformin treatment of osteosarcoma cells enhanced the effects of chemotherapy via suppression of N-cadherin.
SATB2 plays an important role in regulating osteosarcoma stem cell-like properties and tumor growth. The combination of conventional chemotherapy and metformin may be a promising therapeutic strategy for osteosarcoma patients.
研究 SATB2 在骨肉瘤干细胞样特性中的作用，寻找消除骨肉瘤肿瘤干细胞的新策略。
通过悬浮球形成或化疗药物富集的方法获得骨肉瘤肿瘤干细胞。采用 qRT-PCR 和 Western blot 分析骨肉瘤肿瘤干细胞中的 SATB2 和多能性相关基因表达。通过球体形成实验、细胞计数试剂盒-8 检测和抗化疗蛋白检测，评估 SATB2、N-钙黏蛋白表达改变或二甲双胍治疗对肿瘤干细胞的影响。通过裸鼠注射 SATB2 缺陷型 U2OS/MTX 细胞，评估 SATB2 在体内骨肉瘤生长和化疗耐药中的作用。通过生物信息学分析鉴定 SATB2 下游靶基因，通过免疫组化检测 SATB2 表达与患者预后的相关性。通过 Western blot 和荧光素酶报告基因检测，研究 N-钙黏蛋白和 SATB2 抑制对 NF-κB 通路的影响。
SATB2 在骨肉瘤干细胞中上调。SATB2 敲低减少了体外悬浮球形成、细胞增殖和干细胞样基因表达，同时减少了体内肿瘤生长和化疗耐药。骨肉瘤患者样本中 SATB2 的高表达与不良临床预后相关。N-钙黏蛋白是 SATB2 的一个关键下游靶基因，介导了肿瘤干细胞样表型。SATB2 或 N-钙黏蛋白的减少导致 NF-κB 失活，从而削弱了骨肉瘤球体形成和肿瘤细胞增殖。二甲双胍治疗骨肉瘤细胞通过抑制 N-钙黏蛋白增强了化疗效果。
SATB2 在调节骨肉瘤干细胞样特性和肿瘤生长中起重要作用。常规化疗联合二甲双胍可能是骨肉瘤患者有前途的治疗策略。
