Characterization of Δnp73 expression and regulation in gastric and esophageal tumors

A. E. Vilgelm, S. M. Hong, M. K. Washington, J. Wei, H. Chen, Wael El-Rifai, Alexander Zaika

Research output: Contribution to journalArticle

19 Citations (Scopus)

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, ΔNp73, has potent anti-apoptotic and oncogenic properties in vitro and in vivo. In this study, we analyzed, for the first time, the regulation of ΔNp73 in a large number of gastric, gastroesophageal junction and esophageal tumors. We found that expression of ΔNp73 mRNA and protein is increased in these neoplasms. Furthermore, the upregulation of the ΔNp73 protein is significantly associated with poor patient survival. Oncogenic properties of ΔNp73 were further confirmed by finding that ΔNp73 facilitates anchorage-independent growth of gastric epithelial cells in soft agar. As little is currently known about the regulation of ΔNp73 transcription, we investigated the alternative p73 gene promoter that mediates the ΔNp73 expression. Analyzing the ΔNp73 promoter in silico as well as by using chromatin immunoprecipitation, site-directed mutagenesis and deletion analyses, we identified the evolutionary conserved region within the ΔNp73 promoter that contains binding sites for HIC1 (hypermethylated in cancer) protein. We found that HIC1 negatively regulates ΔNp73 transcription in mucosal epithelial cells. This leads to a decrease in ΔNp73 protein levels and may normally control the oncogenic potential of the ΔNp73 isoform.

Original languageEnglish (US)
Pages (from-to)5861-5868
Number of pages8
JournalOncogene
Volume29
Issue number43
DOIs
StatePublished - Oct 28 2010
Externally publishedYes

Fingerprint

Stomach
Protein Isoforms
Neoplasms
Proteins
Epithelial Cells
Esophagogastric Junction
Chromatin Immunoprecipitation
Site-Directed Mutagenesis
Computer Simulation
Agar
Carcinogenesis
Up-Regulation
Binding Sites
Messenger RNA
Survival
Growth
Genes

Keywords

  • esophageal tumor
  • gastric tumor
  • p73

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Characterization of Δnp73 expression and regulation in gastric and esophageal tumors. / Vilgelm, A. E.; Hong, S. M.; Washington, M. K.; Wei, J.; Chen, H.; El-Rifai, Wael; Zaika, Alexander.

In: Oncogene, Vol. 29, No. 43, 28.10.2010, p. 5861-5868.

Research output: Contribution to journalArticle

Vilgelm, A. E. ; Hong, S. M. ; Washington, M. K. ; Wei, J. ; Chen, H. ; El-Rifai, Wael ; Zaika, Alexander. / Characterization of Δnp73 expression and regulation in gastric and esophageal tumors. In: Oncogene. 2010 ; Vol. 29, No. 43. pp. 5861-5868.
@article{d7d61e45645d4836bf7967cd3a17e46b,
title = "Characterization of Δnp73 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, ΔNp73, has potent anti-apoptotic and oncogenic properties in vitro and in vivo. In this study, we analyzed, for the first time, the regulation of ΔNp73 in a large number of gastric, gastroesophageal junction and esophageal tumors. We found that expression of ΔNp73 mRNA and protein is increased in these neoplasms. Furthermore, the upregulation of the ΔNp73 protein is significantly associated with poor patient survival. Oncogenic properties of ΔNp73 were further confirmed by finding that ΔNp73 facilitates anchorage-independent growth of gastric epithelial cells in soft agar. As little is currently known about the regulation of ΔNp73 transcription, we investigated the alternative p73 gene promoter that mediates the ΔNp73 expression. Analyzing the ΔNp73 promoter in silico as well as by using chromatin immunoprecipitation, site-directed mutagenesis and deletion analyses, we identified the evolutionary conserved region within the ΔNp73 promoter that contains binding sites for HIC1 (hypermethylated in cancer) protein. We found that HIC1 negatively regulates ΔNp73 transcription in mucosal epithelial cells. This leads to a decrease in ΔNp73 protein levels and may normally control the oncogenic potential of the ΔNp73 isoform.",
keywords = "esophageal tumor, gastric tumor, p73",
author = "Vilgelm, {A. E.} and Hong, {S. M.} and Washington, {M. K.} and J. Wei and H. Chen and Wael El-Rifai and Alexander Zaika",
year = "2010",
month = "10",
day = "28",
doi = "10.1038/onc.2010.319",
language = "English (US)",
volume = "29",
pages = "5861--5868",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "43",

}

TY - JOUR

T1 - Characterization of Δnp73 expression and regulation in gastric and esophageal tumors

AU - Vilgelm, A. E.

AU - Hong, S. M.

AU - Washington, M. K.

AU - Wei, J.

AU - Chen, H.

AU - El-Rifai, Wael

AU - Zaika, Alexander

PY - 2010/10/28

Y1 - 2010/10/28

N2 - 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 first time, the regulation of ΔNp73 in a large number of gastric, gastroesophageal junction and esophageal tumors. We found that expression of ΔNp73 mRNA and protein is increased in these neoplasms. Furthermore, the upregulation of the ΔNp73 protein is significantly associated with poor patient survival. Oncogenic properties of ΔNp73 were further confirmed by finding that ΔNp73 facilitates anchorage-independent growth of gastric epithelial cells in soft agar. As little is currently known about the regulation of ΔNp73 transcription, we investigated the alternative p73 gene promoter that mediates the ΔNp73 expression. Analyzing the ΔNp73 promoter in silico as well as by using chromatin immunoprecipitation, site-directed mutagenesis and deletion analyses, we identified the evolutionary conserved region within the ΔNp73 promoter that contains binding sites for HIC1 (hypermethylated in cancer) protein. We found that HIC1 negatively regulates ΔNp73 transcription in mucosal epithelial cells. This leads to a decrease in ΔNp73 protein levels and may normally control the oncogenic potential of the ΔNp73 isoform.

AB - 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 first time, the regulation of ΔNp73 in a large number of gastric, gastroesophageal junction and esophageal tumors. We found that expression of ΔNp73 mRNA and protein is increased in these neoplasms. Furthermore, the upregulation of the ΔNp73 protein is significantly associated with poor patient survival. Oncogenic properties of ΔNp73 were further confirmed by finding that ΔNp73 facilitates anchorage-independent growth of gastric epithelial cells in soft agar. As little is currently known about the regulation of ΔNp73 transcription, we investigated the alternative p73 gene promoter that mediates the ΔNp73 expression. Analyzing the ΔNp73 promoter in silico as well as by using chromatin immunoprecipitation, site-directed mutagenesis and deletion analyses, we identified the evolutionary conserved region within the ΔNp73 promoter that contains binding sites for HIC1 (hypermethylated in cancer) protein. We found that HIC1 negatively regulates ΔNp73 transcription in mucosal epithelial cells. This leads to a decrease in ΔNp73 protein levels and may normally control the oncogenic potential of the ΔNp73 isoform.

KW - esophageal tumor

KW - gastric tumor

KW - p73

UR - http://www.scopus.com/inward/record.url?scp=78049338121&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78049338121&partnerID=8YFLogxK

U2 - 10.1038/onc.2010.319

DO - 10.1038/onc.2010.319

M3 - Article

C2 - 20676143

AN - SCOPUS:78049338121

VL - 29

SP - 5861

EP - 5868

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 43

ER -