TIMP3 Overexpression Improves the Sensitivity of Osteosarcoma to Cisplatin by Reducing IL-6 Production.
TIMP3 Overexpression Improves the Sensitivity of Osteosarcoma to Cisplatin by Reducing IL-6 Production.
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DOI：
10.3389/fgene.2018.00135
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发表时间：
2018
影响因子：
3.7
通讯作者：
Tang TT
中科院分区：
文献类型：
--
作者：
Han XG;Mo HM;Liu XQ;Li Y;Du L;Qiao H;Fan QM;Zhao J;Zhang SH;Tang TT
骨肉瘤是儿童和青少年中最常见的骨癌。组织金属蛋白酶抑制剂(TIMPs)-3抑制基质金属蛋白酶限制细胞外基质降解。顺铂是一种广泛应用于骨肉瘤治疗的化疗药物。白细胞介素(IL)-6和TIMP3在骨肉瘤耐药过程中发挥重要作用；然而，它们在这一过程中的关系尚不清楚。本研究旨在探讨TIMP3在骨肉瘤顺铂敏感性中的作用及其体内外分子机制。我们比较了顺铂敏感和不敏感骨肉瘤患者的TIMP3表达水平。TIMP3在Saos2-肺细胞系中过表达或敲低，Saos2是分离自肺转移的Saos2亚型，比Saos2细胞具有更高的顺铂化疗耐药。检测TIMP3过表达或敲低后IL-6的表达、细胞增殖、对顺铂的敏感性、迁移和侵袭。同样的实验用MG63和U2OS细胞进行。随后，将荧光素酶标记的过表达TIMP3的saos2肺细胞注射到顺铂治疗的裸鼠胫骨。结果表明，IL-6通过激活信号转导因子和转录激活因子3 （STAT3）抑制了Saos2和Saos2-肺细胞中TIMP3的表达。STAT3敲低逆转了IL-6的作用。TIMP3在顺铂敏感型骨肉瘤中的表达高于不敏感型骨肉瘤。TIMP3过表达时IL-6表达下调，TIMP3敲低时IL-6表达上调。体外和体内研究表明，TIMP3过表达通过激活凋亡相关信号通路、抑制IL-6表达，抑制细胞增殖，增强顺铂敏感性。综上所述，顺铂敏感性与TIMP3表达呈正相关，TIMP3表达受IL-6/TIMP3/caspase通路调控。TIMP3通路可能成为骨肉瘤治疗新疗法的靶点。
Osteosarcoma is the most common bone cancer in children and adolescents. Tissue inhibitors of metalloproteinases (TIMPs)-3 inhibit matrix metalloproteinases to limit extracellular matrix degradation. Cisplatin is a widely used chemotherapeutic drug used to cure osteosarcoma. Interleukin (IL)-6 and TIMP3 play important roles in the drug resistance of osteosarcoma; however, their relationship in this process remains unclear. This study aimed to explore the role of TIMP3 in the cisplatin sensitivity of osteosarcoma and its underlying molecular mechanisms in vitro and in vivo. We compared TIMP3 expression levels between patients with cisplatin-sensitive and -insensitive osteosarcoma. TIMP3 was overexpressed or knocked down in the Saos2-lung cell line, which is a Saos2 subtype isolated from pulmonary metastases that has higher cisplatin chemoresistance than Saos2 cells. IL-6 expression, cell proliferation, sensitivity to cisplatin, migration, and invasion after TIMP3 overexpression or knockdown were determined. The same experiments were performed using MG63 and U2OS cells. Subsequently, luciferase-labeled Saos2-lung cells overexpressing TIMP3 were injected into the tibiae of nude mice treated with cisplatin. The results showed that IL-6 inhibited TIMP3 expression in Saos2 and Saos2-lung cells via signal transducer and activator of transcription 3 (STAT3) activation. STAT3 knockdown reversed the effect of IL-6. The expression of TIMP3 was higher in patients with cisplatin-sensitive osteosarcoma than in those with insensitive osteosarcoma. IL-6 expression was downregulated upon TIMP3 overexpression, and upregulated by TIMP3 knockdown. TIMP3 overexpression suppressed cell proliferation and enhanced cisplatin sensitivity by activating apoptosis-related signal pathways and inhibiting IL-6 expression in vitro and in vivo. In conclusion, cisplatin sensitivity correlated positively with TIMP3 expression, which is regulated by the IL-6/TIMP3/caspase pathway. The TIMP3 pathway could represent a target for new therapies to treat osteosarcoma.