Analysis of the relationship between the KRAS G12V oncogene and the Hippo effector YAP1 in embryonal rhabdomyosarcoma.,Scientific Reports

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Analysis of the relationship between the KRAS G12V oncogene and the Hippo effector YAP1 in embryonal rhabdomyosarcoma.
Scientific Reports ( IF 3.8 ) Pub Date : 2018-Oct-23 , DOI: 10.1038/s41598-018-33852-7
Abdalla D Mohamed _{1,

2} , Nupur Shah ₁ , Simone Hettmer ₃ , Neil Vargesson ₁ , Henning Wackerhage _{1,

4}

Affiliation

Persistent hyperactivity of the Hippo effector YAP in activated satellite cells is sufficient to cause embryonal rhabdomyosarcoma (ERMS) in mice. In humans, YAP is abundant and nuclear in the majority of ERMS cases, and high YAP expression is associated with poor survival. However, YAP1 is rarely mutated in human ERMS. Instead, the most common mutations in ERMS are oncogenic RAS mutations. First, to compare YAP1 S127A and KRAS G12V-driven rhabdomyosarcomas, we re-analysed gene expression microarray datasets from mouse rhabdomyosarcomas caused by these genes. This revealed that only 20% of the up or downregulated genes are identical, suggesting substantial differences in gene expression between YAP and KRAS-driven rhabdomyosarcomas. As oncogenic RAS has been linked to YAP in other types of cancer, we also tested whether KRAS G12V alone or in combination with loss of p53 and p16 activates YAP in myoblasts. We found that neither KRAS G12V alone nor KRAS G12V combined with loss of p53 and p16 activated Yap or Yap/Taz-Tead1-4 transcriptional activity in C2C12 myoblasts or U57810 cells. In conclusion, whilst oncogenic KRAS mutation might activate Yap in other cell types, we could find no evidence for this in myoblasts because the expression of KRAS G12V expression did not change Yap/Taz activity in myoblasts and there was a limited overlap in gene expression between KRAS G12V and YAP1 S127A-driven tumours.

中文翻译：

胚胎横纹肌肉瘤中KRAS G12V癌基因与Hippo效应子YAP1的关系分析。

激活的卫星细胞中 Hippo 效应子 YAP 的持续过度活跃足以引起小鼠胚胎横纹肌肉瘤 (ERMS)。在人类中，大多数 ERMS 病例中 YAP 含量丰富且位于细胞核，YAP 高表达与生存率低相关。然而，YAP1 在人类 ERMS 中很少发生突变。相反，ERMS 最常见的突变是致癌 RAS 突变。首先，为了比较 YAP1 S127A 和 KRAS G12V 驱动的横纹肌肉瘤，我们重新分析了由这些基因引起的小鼠横纹肌肉瘤的基因表达微阵列数据集。这表明只有 20% 的上调或下调基因是相同的，表明 YAP 和 KRAS 驱动的横纹肌肉瘤之间的基因表达存在显着差异。由于致癌 RAS 与其他类型癌症中的 YAP 相关，因此我们还测试了 KRAS G12V 单独使用或与 p53 和 p16 缺失结合使用是否会激活成肌细胞中的 YAP。我们发现，单独的 KRAS G12V 或 KRAS G12V 与 p53 和 p16 缺失结合都不会激活 C2C12 成肌细胞或 U57810 细胞中的 Yap 或 Yap/Taz-Tead1-4 转录活性。总之，虽然致癌 KRAS 突变可能会在其他细胞类型中激活 Yap，但我们在成肌细胞中找不到证据，因为 KRAS G12V 的表达不会改变成肌细胞中的 Yap/Taz 活性，并且成肌细胞中的基因表达存在有限的重叠。 KRAS G12V 和 YAP1 S127A 驱动的肿瘤。

更新日期：2018-10-23

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