MSI2-TGF-β/TGF-β R1/SMAD3 positive feedback regulation in glioblastoma
MSI2-TGF-β/TGF-β R1/SMAD3 positive feedback regulation in glioblastoma
复制标题
胶质母细胞瘤中的 MSI2-TGF-β/TGF-β R1/SMAD3 正反馈调节
DOI：
10.1007/s00280-019-03892-5
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发表时间：
2019-08-01
影响因子：
3
通讯作者：
Ren, Caiping
中科院分区：
文献类型：
--
作者：
Jiang, Xingjun;Tan, Jun;Ren, Caiping
目的胶质母细胞瘤是恶性程度最高的脑胶质瘤，其复发和化疗耐药是不可避免的，但其化疗耐药的机制仍不完全清楚。本研究旨在探讨胶质母细胞瘤化疗耐药的分子和细胞机制。MSI 2在上皮间质转化（EMT），耐替莫唑胺（TMZ），肿瘤细胞的侵袭，迁移，增殖和相关的信号转导的影响进行了evaluated.ResultsHigh MSI 2的表达观察胶质母细胞瘤组织。MSI 2的沉默或过表达显著影响肿瘤细胞的侵袭、迁移和增殖。MSI 2表达的沉默显著抑制了O 6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）的表达和肿瘤生长，并逆转了异种移植肿瘤模型中对TMZ的耐药性。MSI 2表达通过激活转录因子Snail和TGFβ R1/SMAD 3信号传导来调节EMT。结论我们的研究表明MSI 2-TGFβ/SMAD 3信号传导存在正反馈循环，激活EMT和MGMT，这可能导致胶质母细胞瘤的化疗耐药性。这项研究还表明，MSI 2可能成为胶质母细胞瘤治疗的新靶点。
PurposeGlioblastoma is the most malignant glioma tumors with inevitable relapse and resistance to chemotherapy; however, the mechanisms driving chemoresistance remain to be fully elucidated. This study is to explore the molecular and cellular mechanisms involving in the chemoresistance of glioblastoma.MethodsThe expression of musashi (MSI) RNA-binding protein in the tumor tissues and cells of glioblastoma was measured. The effects of MSI2 in epithelial-to-mesenchymal transition (EMT), resistance to temozolomide (TMZ), tumor cell invasion, migration, and proliferation and associated signaling were evaluated.ResultsHigh MSI2 expression was observed in the glioblastoma tissues. Silencing or overexpression of MSI2 significantly affected tumor cells invasion, migration, and proliferation. Silencing of MSI2 expression significantly inhibitedO6-methylguanine-DNA methyltransferase (MGMT) expression and tumor growth, and reversed resistance to TMZ in xenograft tumor models. MSI2 expression regulated EMT through activating the transcription factors Snail and the TGFβ R1/SMAD3 signaling.ConclusionsOur study demonstrated a positive feedback loop of MSI2-TGFβ/SMAD3 signaling which activates the EMT and MGMT which may contribute to chemoresistance in glioblastoma. This study also highlights that MSI2 could be a new target for the therapy of glioblastoma.