KIT and RAS signalling pathways in testicular germ cell tumours: new data and a review of the literature
KIT and RAS signalling pathways in testicular germ cell tumours: new data and a review of the literature
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DOI：
10.1111/j.1365-2605.2007.00769.x
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发表时间：
2007-08-01
影响因子：
--
通讯作者：
Shipley, J.
中科院分区：
文献类型：
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作者：
Goddard, N. C.;McIntyre, A.;Shipley, J.
睾丸生殖细胞肿瘤（TGCT）是年轻男性白种人癌症死亡的主要原因。识别 DNA 拷贝数的变化可以查明参与肿瘤发展的基因。我们使用阵列比较基因组杂交分析定义了 TGCT 中不平衡的最小重叠区域。确定了新的区域或对先前报道的区域进行改进的区域。 TGCT 中总是获得的 12p 基因的表达谱以及 12p11.2-12.1 和 4q12 定义的扩增子表明 KRAS 和 KIT 分别参与 TGCT 和精原细胞瘤的发展。在与显示这些变化的侵袭性疾病相邻的管内生殖细胞肿瘤中没有发现这些基因的扩增，表明它们参与肿瘤进展。 RAS 基因（KRAS 或 NRAS）的激活突变和 KRAS 的过度表达是相互排斥的事件。 KIT、KRAS 和 GRB7（编码已知与 KIT 酪氨酸激酶受体相互作用的接头分子）表达水平之间的相关性以及此处回顾的其他报道证据，与 KIT 和 RAS 信号传导在 TGCT 发育中激活的作用一致。为了评估 KIT 在精原细胞瘤中的作用，我们调节了精原细胞瘤细胞系 TCam-2 中 KIT 的表达水平。通过证明 KIT 和 OCT3/4 过度表达以及 12p 物质的获得，支持了该细胞系可能的精原细胞起源。通过 RNA 抑制降低 TCam-2 中 KIT 的表达会导致细胞活力下降。对 TGCT 中 KIT 和 RAS 信号传导的进一步了解可能会为这些肿瘤带来新的治疗方法。
Testicular germ cell tumours (TGCTs) are the leading cause of cancer deaths in young male Caucasians. Identifying changes in DNA copy number can pinpoint genes involved in tumour development. We defined the smallest overlapping regions of imbalance in TGCTs using array comparative genomic hybridization analysis. Novel regions, or regions which refined those previously reported, were identified. The expression profile of genes from 12p, which is invariably gained in TGCTs, and amplicons defined at 12p11.2-12.1 and 4q12, suggest KRAS and KIT involvement in TGCT and seminoma development, respectively. Amplification of these genes was not found in intratubular germ cell neoplasia adjacent to invasive disease showing these changes, suggesting their involvement in tumour progression. Activating mutations of RAS genes (KRAS or NRAS) and overexpression of KRAS were mutually exclusive events. These, correlations between the expression levels of KIT, KRAS and GRB7 (which encodes an adapter molecule known to interact with the KIT tyrosine kinase receptor) and other reported evidence reviewed here, are consistent with a role for activation of KIT and RAS signalling in TGCT development. In order to assess a role for KIT in seminomas, we modulated the level of KIT expression in TCam-2, a seminoma cell line. The likely seminomatous origin of this cell line was supported by demonstrating KIT and OCT3/4 overexpression and gain of 12p material. Reducing the expression of KIT in TCam-2 through RNA inhibition resulted in decreased cell viability. Further understanding of KIT and RAS signalling in TGCTs may lead to novel therapeutic approaches for these tumours.