RRC ID 68528
Author Suganuma T, Ino K, Shibata K, Nomura S, Kajiyama H, Kikkawa F, Tsuruoka N, Mizutani S.
Title Regulation of aminopeptidase A expression in cervical carcinoma: role of tumor-stromal interaction and vascular endothelial growth factor.
Journal Lab Invest
Abstract We previously demonstrated that aminopeptidase A (APA), a membrane-bound metallopeptidase degrading bioactive peptides such as angiotensin II (Ang II), is expressed in neoplastic lesions of the uterine cervix, and that its expression is upregulated as the lesion progresses from cervical intraepithelial neoplasms (CIN) toward invasive squamous cell carcinomas (SCC). The present study investigated the regulatory mechanisms involved in APA expression and its potential role in cervical carcinoma. Immunohistochemical staining in high-grade CIN and SCC tissues showed that APA was strongly expressed at the edge of lesions adjacent to cervical stromal cells. Fluorescence-activated cell sorting analysis demonstrated that cell surface APA expression was extremely low in three human SCC cell lines, SiHa, TCS and CaSki, under basal conditions. However, both contact and noncontact cocultures with human cervical fibroblasts resulted in the induction of APA expression in these SCC cells. APA expression was also induced in vivo when TCS cells were subcutaneously inoculated into nude mice. Furthermore, APA expression and enzymatic activity were enhanced by addition of the conditioned medium (CM) from fibroblast culture, but not by heat-treated CM. Among the various cytokines tested, vascular endothelial growth factor (VEGF) significantly increased APA activity, and induction of APA by the fibroblast CM was partly inhibited by anti-VEGF neutralizing antibody. Finally, APA cDNA-transfected APA-overexpressing TCS cells significantly reduced the Ang II-induced cell invasion ability as compared with parental or control vector-transfected TCS cells, although there was no significant difference in cellular proliferation among them. These results suggested the importance of tumor-stromal interaction for the regulation of APA expression in the microenvironment of cervical carcinoma and the potential role for this peptidase in regulating tumor invasion through inactivation of Ang II activity.
Volume 84(5)
Pages 639-48
Published 2004-5-1
DOI 10.1038/labinvest.3700072
PII 3700072
PMID 15048132
MeSH Angiotensin II / pharmacology Animals Cell Division Cell Line, Tumor Cervical Intraepithelial Neoplasia / enzymology Cervical Intraepithelial Neoplasia / pathology Culture Media, Conditioned Female Gene Expression Glutamyl Aminopeptidase / genetics Glutamyl Aminopeptidase / metabolism* Humans Mice Mice, Nude Neoplasm Invasiveness Neoplasm Transplantation Transfection Transplantation, Heterologous Uterine Cervical Neoplasms / enzymology* Uterine Cervical Neoplasms / metabolism Uterine Cervical Neoplasms / pathology Vascular Endothelial Growth Factor A / antagonists & inhibitors Vascular Endothelial Growth Factor A / pharmacology*
IF 4.197
Human and Animal Cells TCS(RCB0638)