The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo
The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo
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DOI：
10.1101/gad.1777409
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发表时间：
2009-06-01
影响因子：
10.5
通讯作者：
Holland, Eric C.
中科院分区：
文献类型：
--
作者：
Huse, Jason T.;Brennan, Cameron;Holland, Eric C.
激活的致癌信号是几乎所有形式的癌症的发展的核心，包括最常见的原发性脑肿瘤，神经胶质瘤。过去二十年的研究已经揭示了Akt通路及其分子拮抗剂PTEN（磷酸酶和张力蛋白同源物）在胶质瘤形成过程中的特别重要性。最近的研究还表明，microRNAs（miRNAs）可能负责肿瘤中与癌症相关的基因的调节。在这里，我们报告的鉴定miR-26 a作为一个直接调节PTEN表达。我们还发现，miR-26 a在人类胶质瘤中经常在DNA水平扩增，最常与单等位基因PTEN缺失相关。最后，我们证明了在小鼠胶质瘤模型中miR-26 a介导的PTEN抑制既增强了肿瘤的新生形成，又排除了杂合性和PTEN基因座的丢失。我们的研究结果证明了胶质瘤中PTEN调控的一种新的表观遗传机制，并进一步强调Akt信号转导的失调对这些肿瘤的发展至关重要。
Activated oncogenic signaling is central to the development of nearly all forms of cancer, including the most common class of primary brain tumor, glioma. Research over the last two decades has revealed the particular importance of the Akt pathway, and its molecular antagonist PTEN (phosphatase and tensin homolog), in the process of gliomagenesis. Recent studies have also demonstrated that microRNAs (miRNAs) may be responsible for the modulation of cancer-implicated genes in tumors. Here we report the identification miR-26a as a direct regulator of PTEN expression. We also show that miR-26a is frequently amplified at the DNA level in human glioma, most often in association with monoallelic PTEN loss. Finally, we demonstrate that miR-26a-mediated PTEN repression in a murine glioma model both enhances de novo tumor formation and precludes loss of heterozygosity and the PTEN locus. Our results document a new epigenetic mechanism for PTEN regulation in glioma and further highlight dysregulation of Akt signaling as crucial to the development of these tumors.