Expression of BARHL1 in medulloblastoma is associated with prolonged survival in mice and humans.
Expression of BARHL1 in medulloblastoma is associated with prolonged survival in mice and humans.
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BARHL1在髓母细胞瘤中的表达与小鼠和人类的长期生存有关。
DOI：
10.1038/onc.2011.173
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发表时间：
2011-11-24
期刊：
影响因子：
8
通讯作者：
Schüller U
中科院分区：
文献类型：
--
作者：
Pöschl J;Lorenz A;Hartmann W;von Bueren AO;Kool M;Li S;Peraud A;Tonn JC;Herms J;Xiang M;Rutkowski S;Kretzschmar HA;Schüller U
髓母细胞瘤是儿童最常见的恶性脑肿瘤，其靶向治疗方法的发展备受关注。尽管恶性转化的分子机制尚不完全清楚，但已知髓母细胞瘤可能起源于小脑颗粒神经元前体。已知同源结构域转录因子Barhl1调节颗粒细胞前体细胞的迁移和存活，但其在髓母细胞瘤中的功能尚不清楚。我们在这里表明，与正常成人小脑相比，BARHL1在人小脑发育过程中和人髓母细胞瘤样本中的表达显著上调。我们还在Math1-cre：SmoM2小鼠的髓母细胞瘤中检测到Barhl1的高水平表达，这是我们之前开发的Sonic Hedgehog相关髓母细胞瘤的小鼠模型。为了研究Barhl1在肿瘤发展过程中的体内功能，我们建立了Barhl1−/−Math1-cre：SmoM2小鼠。有趣的是，在这些小鼠身上形成的肿瘤表现出核分裂活性增加和神经元分化减少。此外，这些小鼠的存活率显著下降。同样，人髓母细胞瘤患者中BARHL1的低表达与患者的预后较差有关。这些结果表明，在人类和小鼠髓母细胞瘤中，Barhl1的表达减缓了肿瘤的生长，应该进一步研究个体化治疗策略的潜在意义。
Medulloblastoma is the most common malignant brain tumor in childhood, and development of targeted therapies is highly desired. Although the molecular mechanisms of malignant transformation are not fully understood, it is known that medulloblastomas may arise from cerebellar granule neuron precursors. The homeodomain transcription factor Barhl1 is known to regulate migration and survival of granule cell precursors, but its functional role in medulloblastoma is unknown. We show here that the expression of BARHL1 is significantly upregulated during human cerebellar development and in human medulloblastoma samples as compared with the normal adult cerebellum. We also detected high levels of Barhl1 expression in medulloblastomas of Math1-cre:SmoM2 mice, a mouse model for Sonic hedgehog-associated medulloblastomas that we developed previously. To investigate Barhl1 function in vivo during tumor development, we generated Barhl1−/−Math1-cre:SmoM2 mice. Interestingly, tumors that developed in these mice displayed increased mitotic activity and decreased neuronal differentiation. Moreover, survival of these mice was significantly decreased. Similarly, low expression of BARHL1 in human medulloblastoma cases was associated with a less favorable prognosis for patients. These results suggest that the expression of Barhl1 decelerates tumor growth both in human and in murine medulloblastomas and should be further investigated with respect to potential implications for individualized therapeutic strategies.