HERC3-Mediated SMAD7 Ubiquitination Degradation Promotes Autophagy-Induced EMT and Chemoresistance in Glioblastoma
HERC3-Mediated SMAD7 Ubiquitination Degradation Promotes Autophagy-Induced EMT and Chemoresistance in Glioblastoma
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HERC3 介导的 SMAD7 泛素化降解促进胶质母细胞瘤中自噬诱导的 EMT 和化疗耐药
DOI：
10.1158/1078-0432.ccr-18-3791
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发表时间：
2019-06-15
影响因子：
11.5
通讯作者：
Lu, Yuntao
中科院分区：
文献类型：
--
作者：
Li, Hong;Li, Junjie;Lu, Yuntao
目的：胶质母细胞瘤是一种常见的颅内恶性肿瘤，预后最差。据报道，自噬通过诱导上皮间质转化（EMT）作为神经胶质瘤中的一种生存促进机制。在这里，我们确定了参与自噬诱导EMT的关键分子，并阐明了放化疗耐药和肿瘤复发的可能机制。实验设计：我们使用同量异位标签进行相对和绝对定量，以鉴定通过自噬诱导剂治疗介导EMT的关键蛋白和通路，并使用胶质瘤和临床胶质母细胞瘤样本以及从核心病变和肿瘤周围区域分离的组织和细胞的组织微阵列测试这些蛋白的表达。对癌症基因组图谱数据库和 110 个胶质母细胞瘤病例的分析揭示了这些分子的预后价值。这些关键分子的功能作用通过体外实验和裸鼠颅内异种移植进一步得到证实。结果：自噬诱导剂显着上调 HERC3 的表达，从而以自溶酶体依赖性方式促进泛素化介导的 SMAD7 降解。 p-SMAD2/3水平的相应增加和TGFβ途径的激活最终诱导细胞系和原代胶质母细胞瘤细胞发生EMT。此外，在肿瘤坏死周围的假栅栏细胞和肿瘤邻近组织中观察到HERC3过度表达。高 HERC3 和低 SMAD7 水平预示着胶质母细胞瘤临床结果不佳；裸鼠异种移植和体外实验证实了这些发现。结论： 总之，我们的研究结果揭示了 HERC3 在调节经典 SMAD2/3 依赖的 TGFβ 通路参与自噬诱导的 EMT 中不可或缺的作用，为更好地理解替莫唑胺耐药和胶质母细胞瘤外周复发的机制提供了见解。
Purpose: Glioblastoma, a common malignant intracranial tumor, has the most dismal prognosis. Autophagy was reported to act as a survival-promoting mechanism in gliomas by inducing epithelial-to-mesenchymal transition (EMT). Here, we determined the critical molecules involved in autophagy-induced EMT and elucidated the possible mechanism of chemoradiotherapy resistance and tumor recurrence. Experimental Design: We used isobaric tags for relative and absolute quantitation to identify the critical proteins and pathway mediating EMT via autophagy inducer treatment, and tested the expression of these proteins using tissue microarray of gliomas and clinical glioblastoma samples as well as tissues and cells separated from the core lesion and tumor-peripheral region. Analysis of the Cancer Genome Atlas database and 110 glioblastoma cases revealed the prognostic value of these molecules. The functional role of these critical molecules was further confirmed by in vitro experiments and intracranial xenograft in nude mice. Results: Autophagy inducers significantly upregulated the expression of HERC3, which promotes ubiquitination-mediated degradation of SMAD7 in an autolysosome-dependent manner. The corresponding increase in p-SMAD2/3 level and TGFβ pathway activation finally induced EMT in cell lines and primary glioblastoma cells. Moreover, HERC3 overexpression was observed in pseudo-palisade cells surrounding tumor necrosis and in tumor-adjacent tissue; high HERC3 and low SMAD7 levels predicted poor clinical outcome in glioblastoma; xenograft of nude mice and in vitro experiments confirmed these findings. Conclusions: Together, our findings reveal the indispensable role of HERC3 in regulating canonical SMAD2/3-dependent TGFβ pathway involvement in autophagy-induced EMT, providing insights toward a better understanding of the mechanism of resistance to temozolomide and peripheral recurrence of glioblastoma.