Aurora-B knockdown inhibits osteosarcoma metastasis by inducing autophagy via the mTOR/ULK1 pathway.
Aurora-B knockdown inhibits osteosarcoma metastasis by inducing autophagy via the mTOR/ULK1 pathway.
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Aurora-B 敲低通过 mTOR/ULK1 途径诱导自噬抑制骨肉瘤转移
DOI：
10.1186/s12935-020-01674-1
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发表时间：
2020-11-30
影响因子：
5.8
通讯作者：
Liu ZL
中科院分区：
文献类型：
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作者：
Wu X;Liu JM;Song HH;Yang QK;Ying H;Tong WL;Zhou Y;Liu ZL
自噬在恶性肿瘤的转移过程中起重要作用。虽然我们的研究表明Aurora-B激酶促进了OS的肺转移，但Aurora-B激酶在OS自噬和肺转移中的作用机制尚未被探讨。收集OS患者的临床病理参数和随访信息。免疫组化法检测OS组织中Aurora-B和LC 3蛋白的表达。短发夹RNA转染用于沉默OS细胞中的Aurora-B。实时定量PCR（RT-qPCR）检测OS细胞Aurora-B mRNA的表达。Western blot检测Aurora-B和自噬相关蛋白的表达。透射电镜和激光扫描共聚焦显微镜观察自噬体和自溶酶体的形成。通过创伤愈合和transwell实验检测OS细胞的迁移和侵袭能力。使用原位异种移植模型来评估Aurora-B抑制介导的自噬对OS肺转移的影响。OS组织中Aurora-B蛋白的表达升高与OS患者的总生存率呈负相关。进一步研究发现，Aurora-B在OS患者组织中的表达与自噬相关蛋白LC 3呈负相关。敲低Aurora-B刺激自噬并抑制OS细胞的迁移和侵袭能力。从机制上讲，Aurora-B敲低抑制mTOR/ULK 1信号通路，mTOR/ULK 1通路的重新激活降低了自噬水平。此外，在体外和体内，沉默Aurora-B对OS迁移和侵袭的抑制作用可被氯喹和mTOR激活剂逆转。我们的研究结果表明，Aurora-B的沉默通过降低mTOR/ULK 1刺激自噬，从而抑制OS转移。靶向Aurora-B/mTOR/ULK 1通路可能是OS患者有希望的治疗策略。
Autophagy plays an essential role in metastasis of malignancies. Although our studies showed that Aurora-B facilitate pulmonary metastasis in OS, the mechanism of Aurora-B kinase on autophagy and metastasis in OS has not been explored. Clinical-pathological parameters and follow-up information was collected in OS patients. Immunohistochemical staining was performed to detect Aurora-B and LC3 protein in OS tissues. Short hairpin RNA transfection was used to silence Aurora-B in OS cells. Real-time quantitative PCR (RT-qPCR) was performed to detect Aurora-B mRNA expression in OS cells. Aurora-B and autophagy related protein were measured by Western blot. Transmission electron microscopy and laser scanning confocal microscopy were performed to observe the formation of autophagosomes and autolysosomes. Migratory and invasive ability of OS cells were measured by Wound healing and transwell assays. Orthotopic xenograft model was used to evaluate the effect of autophagy mediated by Aurora-B inhibition on pulmonary metastasis of OS. The elevated expression of Aurora-B protein in OS tissues negatively associated with the overall survival of OS patients. Further investigation has found that Aurora-B expression was negatively correlative with autophagy related protein LC3 in OS patient tissues. Knockdown Aurora-B stimulates autophagy and inhibits migratory and invasive ability of OS cells. Mechanistically, Aurora-B knockdown suppressed the mTOR/ULK1 signaling pathway and reactivation of the mTOR/ULK1 pathway decreased autophagy level. Furthermore, the inhibition effect of silencing Aurora-B on migration and invasion of OS was reversed by chloroquine and mTOR activator in vitro and vivo. Our results suggest that silencing of Aurora-B stimulate autophagy via decreasing mTOR/ULK1 and result in inhibiting OS metastasis. Targeted Aurora-B/mTOR/ULK1 pathway may be a promising treatment strategy for OS patients.
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影响因子：
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作者：
Bogen D;Wei JS;Azorsa DO;Ormanoglu P;Buehler E;Guha R;Keller JM;Mathews Griner LA;Ferrer M;Song YK;Liao H;Mendoza A;Gryder BE;Sindri S;He J;Wen X;Zhang S;Shern JF;Yohe ME;Taschner-Mandl S;Shohet JM;Thomas CJ;Martin SE;Ambros PF;Khan J
通讯作者：
Khan J
影响因子：
3.1
作者：
Huang, Pei-Yu;Li, Yan;Zhang, Li
通讯作者：
Zhang, Li
影响因子：
7.2
作者：
Chiou, Shiun-Kwei;Hoa, Neil;Jadus, Martin R.
通讯作者：
Jadus, Martin R.
影响因子：
6.4
作者：
Rabanal-Ruiz Y;Otten EG;Korolchuk VI
通讯作者：
Korolchuk VI
影响因子：
--
作者：
Allison DC;Carney SC;Ahlmann ER;Hendifar A;Chawla S;Fedenko A;Angeles C;Menendez LR
通讯作者：
Menendez LR