Human Brat ortholog TRIM3 is a tumor suppressor that regulates asymmetric cell division in glioblastoma.
Human Brat ortholog TRIM3 is a tumor suppressor that regulates asymmetric cell division in glioblastoma.
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DOI：
10.1158/0008-5472.can-13-3703
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发表时间：
2014-08-15
期刊：
影响因子：
11.2
通讯作者：
Brat DJ
中科院分区：
文献类型：
--
作者：
Chen G;Kong J;Tucker-Burden C;Anand M;Rong Y;Rahman F;Moreno CS;Van Meir EG;Hadjipanayis CG;Brat DJ
具有自我更新和多向分化能力的肿瘤干细胞通过对称和不对称细胞分裂的复杂平衡来影响肿瘤行为。调节干细胞及其后代在人类癌症中的动力学的机制知之甚少。在果蝇中，脑肿瘤（brat）突变导致发育中的神经细胞失去正常的不对称细胞分裂，并导致由具有肿瘤性质的成神经细胞组成的大规模扩大的大脑。Brat至少部分通过抑制Myc来促进细胞不对称分裂并指导神经分化。我们鉴定TRIM 3（11p15.5）为果蝇的人类直系同源物，并证明其调节胶质母细胞瘤（GBM）（一种高度恶性的人类脑肿瘤）的不对称细胞分裂和干细胞特性。TRIM 3基因表达在人GBM样品、神经球培养物和细胞系中显著降低，并且其重建损害体外和体内的生长特性。TRIM 3表达减弱原代GBM培养物的干细胞样质量，包括神经球形成和干细胞标志物CD 133、Nestin和Nanog的表达。在GBM干细胞中，TRIM 3表达导致更大百分比的不对称分裂而不是对称分裂。与果蝇中的Brat一样，TRIM 3抑制人类神经胶质瘤细胞系中的c-Myc表达和活性。我们还证明了TRIM 3在GBM神经球和神经干细胞中对Musashi-Notch信号传导的强烈调节，这可能更好地解释其对干细胞动力学的影响。我们得出结论，TRIM 3作为一个肿瘤抑制GBM恢复不对称细胞分裂。
Cancer stem cells, capable of self-renewal and multipotent differentiation, influence tumor behavior through a complex balance of symmetric and asymmetric cell divisions. Mechanisms regulating the dynamics of stem cells and their progeny in human cancer are poorly understood. In Drosophila, mutation of brain tumor (brat) leads to loss of normal asymmetric cell division by developing neural cells and results in a massively enlarged brain composed of neuroblasts with neoplastic properties. Brat promotes asymmetric cell division and directs neural differentiation at least partially through its suppression on Myc. We identified TRIM3 (11p15.5) as a human ortholog of Drosophila brat and demonstrate its regulation of asymmetric cell division and stem cell properties of glioblastoma (GBM), a highly malignant human brain tumor. TRIM3 gene expression is markedly reduced in human GBM samples, neurosphere cultures and cell lines and its reconstitution impairs growth properties in vitro and in vivo. TRIM3 expression attenuates stem-like qualities of primary GBM cultures, including neurosphere formation and the expression of stem cell markers CD133, Nestin and Nanog. In GBM stem cells, TRIM3 expression leads to a greater percentage dividing asymmetrically rather than symmetrically. As with Brat in Drosophila, TRIM3 suppresses c-Myc expression and activity in human glioma cell lines. We also demonstrate a strong regulation of Musashi-Notch signaling by TRIM3 in GBM neurospheres and neural stem cells that may better explain its effect on stem cell dynamics. We conclude that TRIM3 acts as a tumor suppressor in GBM by restoring asymmetric cell division.