RRC ID 61806
Author Yamashita Y, Akatsuka S, Shinjo K, Yatabe Y, Kobayashi H, Seko H, Kajiyama H, Kikkawa F, Takahashi T, Toyokuni S.
Title Met is the most frequently amplified gene in endometriosis-associated ovarian clear cell adenocarcinoma and correlates with worsened prognosis.
Journal PLoS One
Abstract 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.
Volume 8(3)
Pages e57724
Published 2013-1-1
DOI 10.1371/journal.pone.0057724
PII PONE-D-12-27491
PMID 23469222
PMC PMC3587638
MeSH Adenocarcinoma, Clear Cell / complications Adenocarcinoma, Clear Cell / genetics* Adenocarcinoma, Clear Cell / mortality Cell Line, Tumor Comparative Genomic Hybridization Endometriosis / complications Endometriosis / genetics* Endometriosis / mortality Female Gene Expression Regulation, Neoplastic* Humans Neoplasm Staging Ovarian Neoplasms / complications Ovarian Neoplasms / genetics* Ovarian Neoplasms / mortality Phosphatidylinositol 3-Kinases / genetics Prognosis Proto-Oncogene Proteins c-akt / genetics* Proto-Oncogene Proteins c-met / antagonists & inhibitors Proto-Oncogene Proteins c-met / genetics* RNA, Small Interfering / genetics Signal Transduction Survival Analysis
IF 2.74
Human and Animal Cells JHOC-5(RCB1520) JHOC-7(RCB1688) JHOC-8(RCB1723) JHOC-9(RCB2226)