ZIP10 drives osteosarcoma proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway.
ZIP10 drives osteosarcoma proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway.
复制标题
DOI：
10.1186/s13046-021-02146-8
复制
发表时间：
2021-10-27
期刊：
影响因子：
--
通讯作者：
Shen H
中科院分区：
文献类型：
--
作者：
Li H;Shen X;Ma M;Liu W;Yang W;Wang P;Cai Z;Mi R;Lu Y;Zhuang J;Jiang Y;Song Y;Wu Y;Shen H
锌转运蛋白Zrt和Irt相关蛋白（ZIP/SLC 39）在人类肿瘤中过表达，并与预后不良相关;然而，它们对骨肉瘤（OS）的致癌作用和耐药性仍不清楚。我们收集了64例接受化疗（n = 12）或未接受化疗（n = 52）的OS患者组织。采用免疫组化法检测ZIP 10的表达水平，并进行预后分析。在OS细胞系中敲低或过表达ZIP 10以探索其对增殖和化疗抗性的影响。通过RNA测序、实时荧光定量PCR和蛋白质印迹分析来探索ZIP 10调控的下游靶基因。建立异种移植小鼠模型以评估ZIP 10调节OS细胞中的化学抗性的机制。ZIP 10的表达受化疗的诱导，并与OS的临床结局密切相关，ZIP 10的表达下调可抑制OS细胞的增殖和化疗耐药性。此外，ZIP 10促进锌含量诱导的cAMP反应元件结合蛋白（CREB）磷酸化和活化，这是整合素α10（ITGA 10）转录和ITGA 10介导的PI 3 K/AKT通路活化所必需的。重要的是，ITGA 10刺激PI 3 K/AKT信号传导，但不刺激经典的FAK或SRC通路。此外，ZIP 10的过表达促进ITGA 10的表达并赋予化学抗性。用CREB抑制剂666-15或PI 3 K/AKT抑制剂GSK 690693治疗削弱了ZIP 10过表达细胞中的肿瘤化学抗性。最后，通过皮下注射143 B细胞建立的异种移植小鼠模型证实了ZIP 10通过ZIP 10-ITGA 10-PI 3 K/AKT轴介导OS细胞中的化疗抗性。我们证明ZIP 10通过ITGA 10介导的PI 3 K/AKT通路的激活来驱动OS增殖和化学抗性，这可能作为OS治疗的靶点。在线版本包含补充材料，可通过10.1186/s13046-021-02146-8获得。
The zinc transporters Zrt- and Irt-related protein (ZIP/SLC39) are overexpressed in human tumors and correlate with poor prognosis; however, their contributions to carcinogenesis and chemoresistance in osteosarcoma (OS) remain unclear. We collected 64 OS patient tissues with (n = 12) or without (n = 52) chemotherapy. The expression levels of ZIP10 were measured by immunohistochemistry and applied to prognostic analysis. ZIP10 was knocked down or overexpressed in OS cell lines to explore its effect on proliferation and chemoresistance. RNA sequencing, quantitative real-time PCR, and western blotting analysis were performed to explore ZIP10-regulated downstream target genes. A xenograft mouse model was established to evaluate the mechanisms by which ZIP10 modulates chemoresistance in OS cells. The expression of ZIP10 was significantly induced by chemotherapy and highly associated with the clinical outcomes of OS. Knockdown of ZIP10 suppressed OS cell proliferation and chemoresistance. In addition, ZIP10 promoted Zn content-induced cAMP-response element binding protein (CREB) phosphorylation and activation, which are required for integrin α10 (ITGA10) transcription and ITGA10-mediated PI3K/AKT pathway activation. Importantly, ITGA10 stimulated PI3K/AKT signaling but not the classical FAK or SRC pathway. Moreover, overexpression of ZIP10 promoted ITGA10 expression and conferred chemoresistance. Treatment with the CREB inhibitor 666–15 or the PI3K/AKT inhibitor GSK690693 impaired tumor chemoresistance in ZIP10-overexpressing cells. Finally, a xenograft mouse model established by subcutaneous injection of 143B cells confirmed that ZIP10 mediates chemotherapy resistance in OS cells via the ZIP10-ITGA10-PI3K/AKT axis. We demonstrate that ZIP10 drives OS proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway, which might serve as a target for OS treatment. The online version contains supplementary material available at 10.1186/s13046-021-02146-8.
登录
查看更多内容
影响因子：
29.4
作者：
Liu M;Zhang Y;Yang J;Cui X;Zhou Z;Zhan H;Ding K;Tian X;Yang Z;Fung KA;Edil BH;Postier RG;Bronze MS;Fernandez-Zapico ME;Stemmler MP;Brabletz T;Li YP;Houchen CW;Li M
通讯作者：
Li M
影响因子：
5.7
作者：
Jin H;Liu P;Wu Y;Meng X;Wu M;Han J;Tan X
通讯作者：
Tan X
DOI：
10.1016/j.jbc.2021.100320
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Kambe T;Taylor KM;Fu D
通讯作者：
Fu D
DOI：
10.1007/978-94-017-9153-3_4
发表时间：
2014-01-01
期刊：
I DOMAIN INTEGRINS
影响因子：
--
作者：
Lundgren-Akerlund, Evy;Aszodi, Attila
通讯作者：
Aszodi, Attila
影响因子：
5.2
作者：
Sapio L;Salzillo A;Ragone A;Illiano M;Spina A;Naviglio S
通讯作者：
Naviglio S