Met is the most frequently amplified gene in endometriosis-associated ovarian clear cell adenocarcinoma and correlates with worsened prognosis

PLoS One. 2013;8(3):e57724. doi: 10.1371/journal.pone.0057724. Epub 2013 Mar 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • RNA, Small Interfering
  • Phosphatidylinositol 3-Kinases
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • AKT2 protein, human
  • Proto-Oncogene Proteins c-akt

Grant support

This study was supported by a Grant-in-Aid from the Japan Society of the Promotion of Science, Tokyo, Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.