Hedgehog/GLI1 signaling pathway regulates the resistance to cisplatin in human osteosarcoma.
Hedgehog/GLI1 signaling pathway regulates the resistance to cisplatin in human osteosarcoma.
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Hedgehog/GLI1信号通路调控人骨肉瘤顺铂耐药
DOI：
10.7150/jca.61591
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发表时间：
2021
影响因子：
3.9
通讯作者：
Fan P
中科院分区：
文献类型：
--
作者：
Chen D;Kang X;Li Z;Chen L;Ma Q;Fan P
目的：本研究旨在探讨Hedgehog/GLI 1信号通路在骨肉瘤顺铂耐药中的作用及机制。材料与方法：采用免疫组化、western blotting和qRT-PCR方法分析和比较GLI 1在骨肉瘤组织、正常骨组织以及顺铂敏感和耐药细胞系（SOSP-9607和SOSP-9607/CR）中的表达。同时，采用CCK-8、集落形成实验、流式细胞术、创伤愈合实验等方法，通过下调GLI 1的表达，研究GLI 1在OS中的生物学作用。此外，用Western blot分析GLI 1 siRNA和顺铂处理的细胞中GLI 1和γ-H2 AX（DNA损伤蛋白）之间的关系。此外，在移植瘤模型中应用Hedgehog通路抑制剂GANT 61进一步验证GLI 1对OS顺铂耐药的影响及其机制。结果：GLI 1在OS患者和顺铂耐药细胞中表达上调。GLI 1基因沉默显著恢复了OS对顺铂的敏感性，降低了顺铂敏感和耐药细胞的增殖、迁移和克隆能力，增加了体外细胞凋亡率。此外，GANT 61和顺铂的组合施用在小鼠模型中显著抑制肿瘤生长。机制研究发现γ-H2 AX参与顺铂耐药，阻断Hedgehog/GLI 1通路可增加γ-H2 AX的表达。结论：Hedgehog-GLI 1通路的异常激活可调节γ-H2 AX的表达，从而影响DNA损伤和修复功能，促进OS获得性顺铂耐药。
Purpose: This study aimed to investigate the role and mechanism of Hedgehog/GLI1 signaling pathway in regulating the resistance to cisplatin in osteosarcoma (OS). Materials and methods: Immunohistochemistry, western blotting and qRT-PCR assay were performed to analyze and compare the expression of GLI1 in OS tumor tissue and normal bone tissue as well as in cisplatin sensitive and resistant cell lines (SOSP-9607 and SOSP-9607/CR). Meanwhile, the biological role of GLI1 in OS was investigated by using down-regulated expression of GLI1 and functional assays, including CCK-8, colony formation assay, flow cytometry, and wound healing assay. Moreover, the relationship between GLI1 and γ-H2AX (DNA damage protein) in cells treated with GLI1 siRNA and cisplatin was examined using western blot analysis. In addition, GANT61, a inhibitor of Hedgehog pathway was used in xenograft tumor model to further verify the effect and mechanism of GLI1 on cisplatin resistance in OS. Results: We showed that GLI1 expression was up-regulated in OS patients and cisplatin-resistant cells. Silencing GLI1 significantly restored the sensitivity of OS to cisplatin, reduced proliferation, migration and cloning capacity of cisplatin sensitive and resistant cells, and increased the apoptosis rate in vitro. Furthermore, combined administration of GANT61 and cisplatin markedly inhibitted tumor growth in the mouse model. Mechanitic studies found that γ-H2AX is involved in the cisplatin resistance, and blockade of Hedgehog/GLI1 pathway increased the expression of γ-H2AX. Conclusion: Abnormal activation of Hedgehog-GLI1 pathway can regulate the expression of γ-H2AX, thus affecting DNA damage and repair functions, and promoting acquired cisplatin resistance of OS.
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影响因子：
8
作者：
Satheesha S;Manzella G;Bovay A;Casanova EA;Bode PK;Belle R;Feuchtgruber S;Jaaks P;Dogan N;Koscielniak E;Schäfer BW
通讯作者：
Schäfer BW
抑制MARK2通过调节DNA损伤和修复来抑制骨肉瘤干细胞的顺铂耐药性
影响因子：
3.4
作者：
Xu, Liang;Sun, Zhengkao;Li, Jianmin
通讯作者：
Li, Jianmin
影响因子：
3.7
作者：
Urman NM;Mirza A;Atwood SX;Whitson RJ;Sarin KY;Tang JY;Oro AE
通讯作者：
Oro AE
影响因子：
9
作者：
Habel, N.;Hamidouche, Z.;Girault, I.;Patino-Garcia, A.;Lecanda, F.;Marie, P. J.;Fromigue, O.
通讯作者：
Fromigue, O.
细胞外囊泡介导的 miR-101 递送抑制骨肉瘤肺转移
影响因子：
12.4
作者：
Zhang, Kailiang;Dong, Chuan;Zhou, Yong
通讯作者：
Zhou, Yong