Brachyury gene copy number gain and activation of the PI3K/Akt pathway: association with upregulation of oncogenic Brachyury expression in skull base chordoma
Brachyury gene copy number gain and activation of the PI3K/Akt pathway: association with upregulation of oncogenic Brachyury expression in skull base chordoma
复制标题
DOI：
10.3171/2016.12.jns161444
复制
发表时间：
2018-05-01
影响因子：
4.1
通讯作者：
Saito, Nobuhito
中科院分区：
文献类型：
--
作者：
Otani, Ryohei;Mukasa, Akitake;Saito, Nobuhito
目的 脊索瘤是一种生长缓慢的临床恶性肿瘤，许多病例的预后仍然较差。开发更有效的靶向分子疗法具有强大的推动力。在此基础上，作者研究了参与脊索发育的转录因子Brachyury作为治疗脊索瘤的候选分子靶点的潜力。 方法通过定量聚合酶链反应评估27个脊索瘤样本中的Brachyury基因拷贝数和表达水平，以及Brachyury高表达肿瘤（n = 4）和Brachyury低表达肿瘤（n = 4）的转录组 进行了分析。使用脊索瘤细胞系(U-CH2)来研究调节Brachyury表达的信号通路。结果所有脊索瘤标本均表达Brachyury，并且表达水平差异很大。 Brachyury 表达较高的患者的无进展生存期（5 个月，n = 11）明显短于表达较低的患者（13 个月，n = 16）（p = 0.03）。 27 例中有 12 例 (44%) 证实体细胞拷贝数增加，并且拷贝数与 Brachyury 表达呈正相关 (R = 0.61，p < 0.001)。 Brachyury 高表达肿瘤中 PI3K/Akt 通路基因的表达上调，抑制 PI3K 信号传导导致 U-CH2 脊索瘤细胞系中 Brachyury 表达减少并抑制细胞生长。结论 PI3K/Akt 通路的激活和 Brachyury 拷贝数增加与 Brachyury 过表达密切相关，而 Brachyury 过表达似乎是脊索瘤中的关键事件 生长调节。这些发现表明，针对 Brachyury 和 PI3K/Akt 信号传导可能是治疗脊索瘤的有效新方法。
OBJECTIVE Chordoma is a slow-growing but clinically malignant tumor, and the prognosis remains poor in many cases. There is a strong impetus to develop more effective targeted molecular therapies. On this basis, the authors investigated the potential of Brachyury, a transcription factor involved in notochord development, as a candidate molecular target for the treatment of chordoma.METHODS Brachyury gene copy number and expression levels were evaluated by quantitative polymerase chain reaction in 27 chordoma samples, and the transcriptomes of Brachyury high-expression tumors (n = 4) and Brachyury low-expression tumors (n = 4) were analyzed. A chordoma cell line (U-CH2) was used to investigate the signaling pathways that regulate Brachyury expression.RESULTS All chordoma specimens expressed Brachyury, and expression levels varied widely. Patients with higher Brachyury expression had significantly shorter progression-free survival (5 months, n = 11) than those with lower expression (13 months, n = 16) (p = 0.03). Somatic copy number gain was confirmed in 12 of 27 (44%) cases, and copy number was positively correlated with Brachyury expression (R = 0.61, p < 0.001). Expression of PI3K/Akt pathway genes was upregulated in Brachyury high-expression tumors, and suppression of PI3K signaling led to reduced Brachyury expression and inhibition of cell growth in the U-CH2 chordoma cell line.CONCLUSIONS Activation of the PI3K/Akt pathway and Brachyury copy number gain are strongly associated with Brachyury overexpression, which appears to be a key event in chordoma growth regulation. These findings suggest that targeting Brachyury and PI3K/Akt signaling may be an effective new approach for treating chordoma.