Skp2 modulates proliferation, senescence and tumorigenesis of glioma
Skp2 modulates proliferation, senescence and tumorigenesis of glioma
复制标题
Skp2调节神经胶质瘤的增殖、衰老和肿瘤发生
DOI：
10.1186/s12935-020-1144-z
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发表时间：
2020-03-06
影响因子：
5.8
通讯作者：
Wang, Jing
中科院分区：
文献类型：
--
作者：
Wu, Juan;Su, Hong-kai;Wang, Jing
背景胶质瘤是最大的一类原发性中枢神经系统肿瘤，其中许多亚型表现出较差的预后。手术后放疗和化疗已被用作标准策略，但在患者生存结局方面的改善并不令人满意。S-phase kinase protein 2（Skp 2）是E3-连接酶SCF复合物的关键组分，已被证明在各种癌症类型的肿瘤发生中起作用，但其在胶质瘤中的作用尚未完全阐明。本研究旨在探讨Skp 2在胶质瘤增殖、干细胞维持和替莫唑胺（TMZ）药物敏感性中的作用。方法首先分析TCGA和GTEx数据库中Skp 2的表达情况，探讨Skp 2在胶质瘤患者预后中的作用。为了进一步阐明Skp 2对胶质瘤细胞增殖的作用，我们通过敲低和小分子抑制剂（洛伐他汀和SZL-P1 -41）抑制其在胶质母细胞瘤（GBM）细胞系中的水平。然后，我们检测细胞生长，集落形成，球体形成，药物敏感性，并在异种移植小鼠模型体内肿瘤形成。结果Skp 2 mRNA在低级别胶质瘤和GBM中的表达均高于正常脑组织。Skp 2的敲低增加了细胞对TMZ的敏感性，降低了细胞增殖和肿瘤发生。此外，发现Skp 2水平在干细胞富集后增加，而Skp 2的敲低导致球体数目减少。Skp 2的下调也会诱导衰老。洛伐他汀和新化合物SZL-P1 -41的再利用有效地抑制Skp 2，并增强胶质瘤细胞对TMZ的体外和体内敏感性。结论Skp 2在体内外均能调节胶质瘤细胞的增殖、干细胞的维持以及对TMZ的敏感性，提示Skp 2可能成为长期治疗的潜在靶点。
Background Gliomas represent the largest class of primary central nervous system neoplasms, many subtypes of which exhibit poor prognoses. Surgery followed by radiotherapy and chemotherapy has been used as a standard strategy but yielded unsatisfactory improvements in patient survival outcomes. The S-phase kinase protein 2 (Skp2), a critical component of the E3-ligase SCF complex, has been documented in tumorigenesis in various cancer types but its role in glioma has yet to be fully clarified. In this study, we investigated the function of Skp2 in the proliferation, stem cell maintenance, and drug sensitivity to temozolomide (TMZ) of glioma. Methods To investigate the role of Skp2 in the prognosis of patients with glioma, we first analyzed data in databases TCGA and GTEx. To further clarify the effect of Skp2 on glioma cell proliferation, we suppressed its level in glioblastoma (GBM) cell lines through knockdown and small molecule inhibitors (lovastatin and SZL-P1-41). We then detected cell growth, colony formation, sphere formation, drug sensitivity, and in vivo tumor formation in xenograft mice model. Results Skp2 mRNA level was higher in both low-grade glioma and GBM than normal brain tissues. The knockdown of Skp2 increased cell sensitivity to TMZ, decreased cell proliferation and tumorigenesis. In addition, Skp2 level was found increased upon stem cells enriching, while the knockdown of Skp2 led to reduced sphere numbers. Downregulation of Skp2 also induced senescence. Repurposing of lovastatin and novel compound SZL-P1-41 suppressed Skp2 effectively, and enhanced glioma cell sensitivity to TMZ in vitro and in vivo. Conclusion Our data demonstrated that Skp2 modulated glioma cell proliferation in vitro and in vivo, stem cell maintenance, and cell sensitivity to TMZ, which indicated that Skp2 could be a potential target for long-term treatment.