Exploration of genetic alterations in human endometrial cancer and melanoma: distinct tumorigenic pathways that share a frequent abnormal PI3K/AKT cascade.
Exploration of genetic alterations in human endometrial cancer and melanoma: distinct tumorigenic pathways that share a frequent abnormal PI3K/AKT cascade.
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DOI：
10.3892/or.14.6.1481
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发表时间：
2005-12
期刊：
影响因子：
4.2
通讯作者：
Kazumi Ogawa;Chunlan Sun;A. Horii
中科院分区：
文献类型：
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作者：
Kazumi Ogawa;Chunlan Sun;A. Horii
据报道，多种人类肿瘤（包括黑色素瘤和子宫内膜癌）中存在RAS、RAF和PTEN（均为RAS/MAPK和PI 3 K/AKT级联反应的重要成员）的突变。在子宫内膜癌中，已经报道了PTEN和KRAS的互斥突变。另一方面，BRAF的突变是高度频繁的，并且在黑色素瘤中也报道了BRAF和NRAS的互斥突变。本研究通过对RAS/MAPK和PI 3 K/AKT级联反应中的基因和分子的分析，阐明了RAS/MAPK和PI 3 K/AKT级联反应的上调在子宫内膜癌和黑色素瘤发病机制中的作用。分析了12个细胞系，6个黑色素瘤和6个子宫内膜癌; 6个黑色素瘤中的4个（67%）在RAS/MAPK级联中具有基因突变，并且还观察到PTEN表达的降低或丧失。这些结果表明，同时上调这两个级联发挥重要作用，在黑素细胞的癌变。然而，没有观察到磷酸化激活AKT。另一方面，6个子宫内膜癌细胞系中的4个（67%）在这些级联中具有互斥的上调。然而，PI 3 K/AKT级联上调的两个细胞系也在DUSP 6失活诱导的RAS/MAPK级联中上调。这些结果表明，RAS/MAPK和PI 3 K/AKT级联的同时上调是黑素细胞发病机制中的关键事件，而RAS/MAPK或PI 3 K/AKT级联的上调对于大多数子宫内膜癌是至关重要的。
Mutations of RAS, RAF, and PTEN, all important members of the RAS/MAPK and PI3K/AKT cascades, are reported in a variety of human tumors, including melanomas and endometrial cancer. In endometrial cancer, mutually exclusive mutations of PTEN and KRAS have been reported. On the other hand, mutation of BRAF is highly frequent, and mutually exclusive mutations of BRAF and NRAS have also been reported in melanomas. In this study, we elucidated the involvement of the up-regulation of RAS/MAPK and PI3K/AKT cascades in the pathogenesis of endometrial cancer and melanoma by analyzing the genes and molecules in these cascades. Twelve cell lines, six melanoma and six endometrial cancer, were analyzed; 4 (67%) of the 6 melanomas had gene mutations in the RAS/MAPK cascade, and a decrease or loss of PTEN expression was also observed. These results suggested that simultaneous up-regulations in these two cascades play important roles in carcinogenesis of melanocytes. However, no activation of AKT by phosphorylation was observed. On the other hand, 4 (67%) of the 6 endometrial cancer cell lines had mutually exclusive up-regulations in these cascades. However, two cell lines with up-regulation of the PI3K/AKT cascade also had up-regulation in the RAS/MAPK cascade induced by inactivation of DUSP6. These results suggest that simultaneous up-regulation of RAS/MAPK and PI3K/AKT cascades are crucial events in the pathogenesis of melanocytes, whereas up-regulation of either the RAS/MAPK or PI3K/AKT cascade is crucial for the majority of endometrial cancers.