癌变
生物
癌症研究
基因复制
比较基因组杂交
基因敲除
基因
恶性转化
PTEN公司
分子生物学
PI3K/AKT/mTOR通路
细胞凋亡
遗传学
基因组
作者
Yoshihisa Yamashita,Shinya Akatsuka,Kanako Shinjo,Yasushi Yatabe,Hiroharu Kobayashi,Hiroshi Seko,Hiroaki Kajiyama,Fumitaka Kikkawa,Takashi Takahashi,Shinya Toyokuni
出处
期刊:PLOS ONE
[Public Library of Science]
日期:2013-03-04
卷期号:8 (3): e57724-e57724
被引量:70
标识
DOI:10.1371/journal.pone.0057724
摘要
Clear cell adenocarcinoma of the ovary (OCC) is a chemo-resistant tumor with a relatively poor prognosis and is frequently associated with endometriosis. Although it is assumed that oxidative stress plays some role in the malignant transformation of this tumor, the characteristic molecular events leading to carcinogenesis remain unknown. In this study, an array-based comparative genomic hybridization (CGH) analysis revealed Met gene amplification in 4/13 OCC primary tumors and 2/8 OCC cell lines. Amplification of the AKT2 gene, which is a downstream component of the Met/PI3K signaling pathway, was also observed in 5/21 samples by array-based CGH analysis. In one patient, both the Met and AKT2 genes were amplified. These findings were confirmed using fluorescence in situ hybridization, real-time quantitative PCR, immunoblotting, and immunohistochemistry. In total, 73 OCC cases were evaluated using real-time quantitative PCR; 37.0% demonstrated Met gene amplification (>4 copies), and 8.2% had AKT2 amplification. Furthermore, stage 1 and 2 patients with Met gene amplification had significantly worse survival than patients without Met gene amplification (p<0.05). Met knockdown by shRNA resulted in reduced viability of OCC cells with Met amplification due to increased apoptosis and cellular senescence, suggesting that the Met signaling pathway plays an important role in OCC carcinogenesis. Thus, we believe that targeted inhibition of the Met pathway may be a promising treatment for OCC.
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