Dataset Information

Characterization of ?Np73 expression and regulation in gastric and esophageal tumors.

ABSTRACT: p73 is a member of the p53 protein family. Although the tumor suppressor function of p53 is clearly defined, the role of p73 in tumorigenesis is still a matter of debate. A complex pattern of expression of p73 isoforms makes it difficult to unambiguously interpret the experimental results. Previously, we along with others have found that the N-terminally truncated isoform of p73, ?Np73, has potent anti-apoptotic and oncogenic properties in vitro and in vivo. In this study, we analyzed, for the first time, the regulation of ?Np73 in a large number of gastric, gastroesophageal junction and esophageal tumors. We found that expression of ?Np73 mRNA and protein is increased in these neoplasms. Furthermore, the upregulation of the ?Np73 protein is significantly associated with poor patient survival. Oncogenic properties of ?Np73 were further confirmed by finding that ?Np73 facilitates anchorage-independent growth of gastric epithelial cells in soft agar. As little is currently known about the regulation of ?Np73 transcription, we investigated the alternative p73 gene promoter that mediates the ?Np73 expression. Analyzing the ?Np73 promoter in silico as well as by using chromatin immunoprecipitation, site-directed mutagenesis and deletion analyses, we identified the evolutionary conserved region within the ?Np73 promoter that contains binding sites for HIC1 (hypermethylated in cancer) protein. We found that HIC1 negatively regulates ?Np73 transcription in mucosal epithelial cells. This leads to a decrease in ?Np73 protein levels and may normally control the oncogenic potential of the ?Np73 isoform.

SUBMITTER: Vilgelm AE

PROVIDER: S-EPMC4152004 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Characterization of ΔNp73 expression and regulation in gastric and esophageal tumors.

Vilgelm A E AE Hong S-M SM Washington M K MK Wei J J Chen H H El-Rifai W W Zaika A A

Oncogene 20100802 43

p73 is a member of the p53 protein family. Although the tumor suppressor function of p53 is clearly defined, the role of p73 in tumorigenesis is still a matter of debate. A complex pattern of expression of p73 isoforms makes it difficult to unambiguously interpret the experimental results. Previously, we along with others have found that the N-terminally truncated isoform of p73, ΔNp73, has potent anti-apoptotic and oncogenic properties in vitro and in vivo. In this study, we analyzed, for the f ...[more]

PMID: 20676143

Similar Datasets

Project description:Background & aimsIn patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with the development of type 1 gastric neuroendocrine tumors (gNETs). Twelve months of treatment with netazepide (YF476), an antagonist of the cholecystokinin B receptor (CCKBR or CCK2R), eradicated some type 1 gNETs in patients. We investigated the mechanisms by which netazepide induced gNET regression using gene expression profiling.MethodsWe obtained serum samples and gastric corpus biopsy specimens from 8 patients with hypergastrinemia and type 1 gNETs enrolled in a phase 2 trial of netazepide. Control samples were obtained from 10 patients without gastric cancer. We used amplified and biotinylated sense-strand DNA targets from total RNA and Affymetrix (Thermofisher Scientific, UK) Human Gene 2.0 ST microarrays to identify differentially expressed genes in stomach tissues from patients with type 1 gNETs before, during, and after netazepide treatment. Findings were validated in a human AGSGR gastric adenocarcinoma cell line that stably expresses human CCK2R, primary mouse gastroids, transgenic hypergastrinemic INS-GAS mice, and patient samples.ResultsLevels of pappalysin 2 (PAPPA2) messenger RNA were reduced significantly in gNET tissues from patients receiving netazepide therapy compared with tissues collected before therapy. PAPPA2 is a metalloproteinase that increases the bioavailability of insulin-like growth factor (IGF) by cleaving IGF binding proteins (IGFBPs). PAPPA2 expression was increased in the gastric corpus of patients with type 1 gNETs, and immunohistochemistry showed localization in the same vicinity as CCK2R-expressing enterochromaffin-like cells. Up-regulation of PAPPA2 also was found in the stomachs of INS-GAS mice. Gastrin increased PAPPA2 expression with time and in a dose-dependent manner in gastric AGSGR cells and mouse gastroids by activating CCK2R. Knockdown of PAPPA2 in AGSGR cells with small interfering RNAs significantly decreased their migratory response and tissue remodeling in response to gastrin. Gastrin altered the expression and cleavage of IGFBP3 and IGFBP5.ConclusionsIn an analysis of human gNETS and mice, we found that gastrin up-regulates the expression of gastric PAPPA2. Increased PAPPA2 alters IGF bioavailability, cell migration, and tissue remodeling, which are involved in type 1 gNET development. These effects are inhibited by netazepide.

Project description:INTRODUCTION: The polymeric immunoglobulin receptor (PIGR) has been proposed to be a candidate prognostic biomarker in a few cancer forms, and one previous study reported that reduced PIGR expression signifies more aggressive tumours of the distal esophagus and gastroesophageal junction (GEJ). In the present study, we examined the expression, clinicopathological correlates and prognostic significance of PIGR expression in an extended cohort of adenocarcinoma of the upper gastrointestinal tract. MATERIALS AND METHODS: Immunohistochemical PIGR expression was examined in a consecutive cohort of patients with surgically resected, radio-chemonaive adenocarcinoma of the esophagus, GE-junction and stomach (n?=?173), including paired samples of benign-appearing squamous epithelium (n?=?51), gastric mucosa (n?=?114), Barrett's esophagus (BE) or intestinal metaplasia (IM) (n?=?57) and lymph node metastases (n?=?75). Non-parametric tests were applied to explore associations between PIGR expression in primary tumours and clinicopathological characteristics. Classification and regression tree analysis was applied for selection of prognostic cut-off. The impact of PIGR expression on overall survival (OS) and recurrence-free survival (RFS) was assessed by Kaplan-Meier analysis and hazard ratios (HR) calculated by adjusted and unadjusted Cox proportional hazards modelling. RESULTS: PIGR expression was significantly higher in intestinal metaplasia (BE or gastric IM) compared to normal tissues and cancer (p?<?0.001). Reduced PIGR expression in primary tumours was significantly associated with more advanced tumour stage (p?=?0.002) and inversely associated with involved margins (p?=?0.034). PIGR expression did not differ between primary tumours and lymph node metastases. There was no significant difference in PIGR expression between tumours with and without a background of intestinal metaplasia. High PIGR expression was an independent predictor of a prolonged OS (HR?=?0.60, 95% CI 0.36-0.99) and RFS (HR?=?0.49, 95% CI 0.27-0.90) in patients with radically resected (R0) primary tumours and of an improved RFS (HR?=?0.32, 95% CI 0.15-0.69) in curatively treated patients with R0 resection/distant metastasis-free disease. CONCLUSION: High PIGR expression independently predicts a decreased risk of recurrence and an improved survival in patients with adenocarcinoma of the upper gastrointestinal tract. These findings are of potential clinical relevance and merit further validation.

Dataset Information

Characterization of ?Np73 expression and regulation in gastric and esophageal tumors.

Publications

Characterization of ΔNp73 expression and regulation in gastric and esophageal tumors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets