Reduced Expression of Plakoglobin Correlates with Adverse Outcome in Patients with Neuroblastoma

Tel Aviv University, Tell Afif, Tel Aviv, Israel
American Journal Of Pathology (Impact Factor: 4.59). 08/2001; 159(1):43-9. DOI: 10.1016/S0002-9440(10)61671-9
Source: PubMed


Plakoglobin and its homologue beta-catenin are cytoplasmic proteins that mediate adhesive functions by interacting with cadherin receptors and signaling activities by interacting with transcription factors. It has been suggested that plakoglobin can suppress tumorigenicity whereas beta-catenin can act as an oncogene. We investigated the correlation between the expression pattern of N-cadherin, beta-catenin, and plakoglobin and tumor behavior in primary tumors of 20 neuroblastoma patients of all stages and in 11 human neuroblastoma cell lines. N-cadherin and beta-catenin were detected in 9 of 11 and 11 of 11 cell lines, respectively, whereas plakoglobin was undetectable or severely reduced in 6 of 11 cell lines. Tumor cells from 16 of 20 patients expressed N-cadherin and 20 of 20 patients expressed beta-catenin at levels similar to those of normal ganglion cells. Plakoglobin was undetectable in 9 of 20 tumors. Plakoglobin deficiency in the primary tumors was significantly associated with adverse clinical outcome. Five of the patients with plakoglobin-negative tumors died whereas four patients are alive without evident disease. In contrast, all patients with plakoglobin-positive tumors are alive; 2 of 11 are alive with the disease and 9 of 11 are alive without evident disease. These results suggest that down-regulation of plakoglobin may be of prognostic value for neuroblastoma patients as predictor of poor outcome.

Download full-text


Available from: Avri Ben-Ze'ev
  • Source
    • "et al . 2005 ) . However , although we confirmed frequent EMP3 promoter methylation in neuroblastoma , EMP3 methylation did not appear to make a significant contribution to phaeochromocytoma tumourigenesis . Infrequent , or absent , promoter methylation was found for CTNNG ( g - catenin , also known as JUP ) and SYK in phaeochromocytoma . Although Amitay et al . ( 2001 ) reported reduced expression of CTNNG in 9 / 20 neuro - blastoma tumours , we observed promoter methylation in only 11% of neuroblastoma tumours and did not detect promoter methylation in the cell lines that demonstrated an increase expression of CTNNG after 5 - aza - dC treatment . This suggests that promoter methylation of CTNNG does"
    [Show abstract] [Hide abstract]
    ABSTRACT: The molecular genetics of inherited phaeochromocytoma have received considerable attention, but the somatic genetic and epigenetic events that characterise tumourigenesis in sporadic phaeochromocytomas are less well defined. Previously, we found considerable overlap between patterns of promoter region tumour suppressor gene (TSG) hypermethylation in two neural crest tumours, neuroblastoma and phaeochromocytoma. In order to identify candidate biomarkers and epigenetically inactivated TSGs in phaeochromocytoma and neuroblastoma, we characterised changes in gene expression in three neuroblastoma cell lines after treatment with the demethylating agent 5-azacytidine. Promoter region methylation status was then determined for 28 genes that demonstrated increased expression after demethylation. Three genes HSP47, homeobox A9 (HOXA9) and opioid binding protein (OPCML) were methylated in >10% of phaeochromocytomas (52, 17 and 12% respectively). Two of the genes, epithelial membrane protein 3 (EMP3) and HSP47, demonstrated significantly more frequent methylation in neuroblastoma than phaeochromocytoma. These findings extend epigenotype of phaeochromocytoma and identify candidate genes implicated in sporadic phaeochromocytoma tumourigenesis.
    Full-text · Article · May 2008 · Endocrine Related Cancer
  • Source
    • "expression linked to clinical outcome in different tumour types (Pantel et al, 1998; Amitay et al, 2001; Papergerakis et al, 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The reduction or loss of plakoglobin expression in late-stage bladder cancer has been correlated with poor survival where upregulation of this catenin member by histone deacetylase inhibitors has been shown to accompany tumour suppression in an in vivo model. In this study, we directly addressed the question of the role of plakoglobin in bladder tumorigenesis following restoration, or knockdown of expression in bladder carcinoma cell lines. Restoration of plakoglobin expression resulted in a reduction in migration and suppression of tumorigenic potential in vivo. Immunocytochemistry revealed cytoplasmic and membranous localisation of plakoglobin in transfectants with < 1% of cells displaying detectable nuclear localisation of plakoglobin. siRNA knockdown experiments targeting plakoglobin, revealed enhanced migration in all cell lines in the presence and absence of E-cadherin expression. In bladder cell lines expressing low levels of plakoglobin and desmoglein-2, elevated levels of desmoglein-2 were detected following restoration of plakoglobin expression in transfected cell lines. Analysis of wnt signalling revealed no activation event associated with plakoglobin expression in the bladder model. These results show that plakoglobin acts as a tumour suppressor gene in bladder carcinoma cells and the silencing of plakoglobin gene expression in late-stage bladder cancer is a primary event in tumour progression.
    Full-text · Article · Jul 2005 · British Journal of Cancer
  • Source
    • "In some cases such as prostate (Morita et al., 1999), oesophageal (Nakanishi et al., 1997), and non-small cell lung cancer (Pirinen et al., 2001) this appears to be a part of a general loss of expression of AJ components, whilst in others such as neuroblastoma, one of the most common extracranial solid tumours in children, only PG is affected (Amitay et al., 2001). A tumour suppressor role for PG is also inferred from the loss of heterozygosity (LOH) that has been observed at the PG locus on chromosome 17q21 in some sporadic breast and ovarian cancers (Aberle et al., 1995). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Desmosomes play a critical role in the maintenance of normal tissue architecture. Skin blistering can occur when desmosomal adhesion is compromised by antibodies in autoimmune diseases such as pemphigus. Inherited mutations in genes encoding desmosomal constituents can adversely affect the skin, and result in heart abnormalities. Desmosomes may have a tumour suppressor function: expression of desmosomal components is reduced in some human cancers, and desmosomal cadherins have the capacity to suppress the invasiveness of cells in culture. Transgenic animal research has provided important insights into the role of these junctions in normal epithelial morphogenesis and disease.
    Preview · Article · Nov 2002 · Histology and histopathology
Show more