The NMD mRNA surveillance pathway downregulates aberrant E-cadherin transcripts in gastric cancer cells and in CDH1 mutation carriers

• Type: Article in International Scientific Journal
• Date: 2008

Authors

Karam R (Author) Other; Carvalho J (Author) Other; Bruno I (Author) Other; Graziadio C (Author) Other; Senz J (Author) Other; Huntsman D (Author) Other; Carneiro F (Author) FMUP; Seruca R (Author) FMUP; Wilkinson MF (Author) Other; Oliveira C (Author) FMUP

Journal

Title: Oncogene

Vol. 27 No. 30

Pages: 4255-4260

ISSN: 0950-9232

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 57 Citations

Scopus - 59 Citations

Other information

Authenticus ID: P-003-Y9V

DOI: 10.1038/onc.2008.62

Abstract (EN): Germline mutations in the gene encoding the tumour suppressor E-cadherin (CDH1) are the underlying genetic defect responsible for hereditary diffuse gastric cancer (HDGC). A remarkably high percentage (similar to 80%) of CDH1 mutations in HDGC patients and carriers generate premature termination codons (PTCs). Here, we examined whether CDH1 transcripts harbouring PTCs are downregulated by nonsense-mediated decay (NMD), an RNA surveillance pathway that degrades PTC-bearing transcripts. Using an allele-specific expression (ASE) assay to differentiate between mutated and wild-type CDH1 alleles, we found that PTC-bearing CDH1 mRNAs are strongly downregulated in normal gastric tissue from several CDH1 mutation carriers. We show that NMD is responsible for this robust downregulation, as CDH1 transcripts harbouring PTCs in the KATO-III gastric tumour cell line were upregulated in response to protein synthesis inhibitors or depletion of the NMD factors UPF1 and eIF4AIII. Analysis of HDGC patients harbouring CDH1 alleles with PTCs at a wide variety of different positions indicates an association of their predicted ability to induce NMD and an earlier age of onset of gastric cancer. This suggests that NMD may be detrimental for HDGC patients and therefore NMD is a potentially useful therapeutic target for CDH1 mutation carriers.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 6