Met Is the Most Frequently Amplified Gene in Endometriosis-Associated Ovarian Clear Cell Adenocarcinoma and Correlates with Worsened Prognosis

被引:60
|
作者
Yamashita, Yoriko [1 ,2 ]
Akatsuka, Shinya [1 ]
Shinjo, Kanako [1 ,3 ]
Yatabe, Yasushi [4 ]
Kobayashi, Hiroharu [1 ,3 ]
Seko, Hiroshi [1 ]
Kajiyama, Hiroaki [3 ]
Kikkawa, Fumitaka [3 ]
Takahashi, Takashi [5 ]
Toyokuni, Shinya [1 ]
机构
[1] Nagoya Univ, Grad Sch Med, Dept Pathol & Biol Responses, Nagoya, Aichi 4648601, Japan
[2] Nagoya City Univ Hosp, Dept Pathol, Nagoya, Aichi, Japan
[3] Nagoya Univ, Grad Sch Med, Dept Obstet & Gynecol, Nagoya, Aichi 4648601, Japan
[4] Aichi Canc Ctr Hosp, Dept Pathol & Mol Diagnost, Nagoya, Aichi 464, Japan
[5] Nagoya Univ, Grad Sch Med, Ctr Neurol Dis & Canc, Div Mol Carcinogenesis, Nagoya, Aichi 4648601, Japan
来源
PLOS ONE | 2013年 / 8卷 / 03期
关键词
SMALL-MOLECULE INHIBITOR; C-MET; TYROSINE KINASE; POOR-PROGNOSIS; AMPLIFICATION; OVEREXPRESSION; CANCER; EXPRESSION; MUTATIONS; RECEPTOR;
D O I
10.1371/journal.pone.0057724
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
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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页数:11
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