Abstract 191: Dysregulated FBI-1 in gestational trophoblastic neoplasms
Authors: Mak Victor CY , Ng Wai-Yan , Jiang Li-li , Siu Michelle KY , Wong Oscar GW , Ngan Hextan YS , Cheung Annie NY 
Published: July 2012

Background: Human placental trophoblast is considered as a pseudo-malignant tissue. Gestational trophoblastic disease (GTD) includes true malignancies such as choriocarcinomas and potentially malignant hydatidiform moles, which may develop into persistent gestational trophoblastic neoplasms requiring chemotherapy. FBI-1 (also called Pokemon/ZBTB7A) is a BTB/POZ-domain Krüppel-like zinc-finger transcription factor which can inactivate p53 through the ARF-MDM2-p53 pathway. This study investigated the expression and functional effects of FBI-1 in choriocarcinomas as compared with normal placenta and hydatidiform moles.

Methods and Results: Twelve choriocarcinomas, 33 placentas and 53 hydatidiform moles were studied. Quantitative PCR and immunohistochemical analysis demonstrated higher FBI-1 mRNA and protein expression in choriocarcinoma and hydatidiform moles when compared with normal placentas (p&lt;0.05). Significantly higher FBI-1 expression was found in hydatidiform moles that progressed to persistent gestational trophoblastic neoplasms than in those regressed (P=0.032). FBI-1 immunoreactivity correlated significantly with that of p53, p21WAF1/CIP1 and PTEN (P&lt;0.05). p21WAF1/CIP1 is a cyclin dependent kinase and downstream effector of p53 while PTEN is another tumour suppressor that physically and genetically interacts with p53. Ectopic expression of FBI-1 in choriocarcinoma cells, JEG-3 and JAR, inhibited apoptosis in vitro as revealed by TUNEL assays and repressed mRNA expressions of apoptotic genes in both intrinsic and extrinsic pathways including Bak, Fas and caspase-8. Proliferation and cell invasion/migration enhancing effects was found by MTT assay and transwell assays after FBI-1 transfection. The mechanisms governing increased expression of FBI-1 in choriocarcinoma were investigated. Histone deacetylase inhibitor Trichostatin A was found to induce FBI-1 mRNA expression in both JEG-3 and JAR choriocarcinoma cell lines. A borderline correlation between RNA level and DNA copy of FBI-1 expression was also detected while FBI-1 expression was not affected by treatment with MG132, an ubiquitination inhibitor. Due to the observed inhibitory effect of FBI-1 on apoptosis, possible interaction between FBI-1 and other p53 related proteins was further investigated. iASPP is a recently identified wild-type p53 binding protein that inhibits p53-dependent apoptosis. Anti-FBI-1 was able to pull-down iASPP in JEG-3 as demonstrated by co-immunoprecipitation study, indicating possible interaction between these two transcriptional regulators.

Conclusions: FBI-1 upregulation was associated with frankly malignant choriocarcinoma and hydatidiform moles of aggressive behaviour. Aberrant FBI-1 expression, related to histone acetylation and gene amplification, displays diverse effects on cell proliferation, apoptosis and invasion probably thorough interaction in transcriptional complex.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 191. doi:10.1158/1538-7445.AM2011-191