Human placental trophoblasts can be considered pseudomalignant, with tightly controlled proliferation, apoptosis, and invasiveness. Gestational trophoblastic disease (GTD) represents a family of heterogeneous trophoblastic lesions with aberrant apoptotic and proliferative activities and dysregulation of cell signaling pathways. We characterize the oncogenic effects of factor that binds to the inducer of short transcripts of HIV-1 [FBI-1, alias POZ and Krüppel erythroid myeloid ontogenic factor (POKEMON)/ZBTB7A] in GTD and its role in promoting cell aggressiveness in vitro and tumor growth in vivo. IHC studies showed increased nuclear expression of FBI-1, including hydatidiform moles, choriocarcinoma (CCA), and placental site trophoblastic tumor, in GTD. In JAR and JEG-3 CCA cells, ectopic FBI-1 expression opposed apoptosis through repression of proapoptotic genes (eg, BAK1, FAS, and CASP8). FBI-1 overexpression also promoted Akt activation, as indicated by Akt-pS473 phosphorylation. FBI-1 overexpression promoted mobility and invasiveness of JEG-3 and JAR, but not in the presence of the phosphoinositide 3-kinase inhibitor LY294002. These findings suggest that FBI-1 could promote cell migration and invasion via phosphoinositide 3-kinase/Akt signaling. In vivo, nude mice injected with CCA cells with stable FBI-1 knockdown demonstrated reduced tumor growth compared with that in control groups. These findings suggest that FBI-1 is clinically associated with the progression of, and may be a therapeutic target in, GTD, owing to its diverse oncogenic effects on dysregulated trophoblasts.
Pyroglutamic acidosis (PGA) is an underrecognized entity characterised by raised anion gap metabolic acidosis (RAGMA) and urinary hyper-excretion of pyroglutamic acid. It is frequently associated with chronic acetaminophen (APAP) ingestion. We report the case of a 73-year-old man with invasive pulmonary aspergillosis treated with voriconazole, and APAP for analgesia with a cumulative dose of 160g over 40 days. PGA was suspected as he developed severe RAGMA and which common causes were excluded. Diagnosis was confirmed by urinary organic acid analysis showing significant hyper-excretion of pyroglutamic acid. APAP was discontinued and N-acetylcysteine (NAC) was administered. His RAGMA rapidly resolved following treatment.
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<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<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
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