SERPINB3 in the chicken model of ovarian cancer: a prognostic factor for platinum resistance and survival in patients with epithelial ovarian cancer

PLoS One. 2012;7(11):e49869. doi: 10.1371/journal.pone.0049869. Epub 2012 Nov 21.

Abstract

Serine protease inhibitors (SERPINs) appear to be ubiquitously expressed in a variety of species and play important roles in pivotal physiological processes such as angiogenesis, immune responses, blood coagulation and fibronolysis. Of these, squamous cell carcinoma antigen 1 (SCCA1), also known as a SERPINB3, was first identified in squamous cell carcinoma tissue from the cervix of women. However, there is little known about the SERPINB3 expression in human epithelial ovarian cancer (EOC). Therefore, in the present study, we investigated the functional role of SERPINB3 gene in human EOC using chickens, the most relevant animal model. In 136 chickens, EOC was found in 10 (7.4%). SERPINB3 mRNA was induced in cancerous, but not normal ovaries of chickens (P<0.01), and it was abundant only in the glandular epithelium of cancerous ovaries of chickens. Further, several microRNAs, specifically miR-101, miR-1668 and miR-1681 were discovered to influence SERPINB3 expression via its 3'-UTR which suggests that post-transcriptional regulation influences SERPINB3 expression in chickens. SERPINB3 protein was localized predominantly to the glandular epithelium in cancerous ovaries of chickens, and it was abundant in the nucleus of both chicken and human ovarian cancer cell lines. In 109 human patients with EOC, 15 (13.8%), 66 (60.6%) and 28 (25.7%) patients showed weak, moderate and strong expression of SERPINB3 protein, respectively. Strong expression of SERPINB3 protein was a prognostic factor for platinum resistance (adjusted OR; odds ratio, 5.94; 95% Confidence Limits, 1.21-29.15), and for poor progression-free survival (PFS; adjusted HR; hazard ratio, 2.07; 95% CI; confidence interval, 1.03-4.41). Therefore, SERPINB3 may play an important role in ovarian carcinogenesis and be a novel biomarker for predicting platinum resistance and a poor prognosis for survival in patients with EOC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antigens, Neoplasm* / genetics
  • Antigens, Neoplasm* / immunology
  • Carcinoma, Ovarian Epithelial
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • Chickens / genetics
  • Chickens / immunology
  • Disease Models, Animal
  • Disease-Free Survival
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Middle Aged
  • Neoplasm Staging
  • Neoplasms, Glandular and Epithelial* / drug therapy
  • Neoplasms, Glandular and Epithelial* / genetics
  • Neoplasms, Glandular and Epithelial* / metabolism
  • Neoplasms, Glandular and Epithelial* / pathology
  • Ovarian Neoplasms* / drug therapy
  • Ovarian Neoplasms* / genetics
  • Ovarian Neoplasms* / metabolism
  • Ovarian Neoplasms* / pathology
  • Ovary* / metabolism
  • Ovary* / pathology
  • Platinum / therapeutic use
  • Prognosis*
  • Serine Proteinase Inhibitors / administration & dosage
  • Serpins* / genetics
  • Serpins* / immunology

Substances

  • 3' Untranslated Regions
  • Antigens, Neoplasm
  • Serine Proteinase Inhibitors
  • Serpins
  • squamous cell carcinoma-related antigen
  • Platinum

Grant support

This research was funded by the World Class University (WCU) program (R31-10056) and by Basic Science Research Program (2010-0013078) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology, and also by a grant from the Next-Generation BioGreen 21 Program (No. PJ008142), Rural Development Administration, Republic of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.