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

Abstract

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 (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.

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Acknowledgements

We thank the family members who collaborated in this study. We thank Dr Marjolijn Ligtenberg from Department of Human Genetics, University Medical Centre Nijmegen, NL and Dr Han van Krieken from Radboud University Nijmegen Medical Center, NL, for providing patients’ material. We also thank G.A.B.B.A. Program at University of Porto, FLAD, CAPES and GRICES. This work was supported by grants from FCT (POCTI/SAU-OBS/58111/2004 and SFRH/BD/15241/2004) and NIH (5-RO1GM058595-08).

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Correspondence to M F Wilkinson or C Oliveira.

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Karam, R., Carvalho, J., Bruno, I. et al. The NMD mRNA surveillance pathway downregulates aberrant E-cadherin transcripts in gastric cancer cells and in CDH1 mutation carriers. Oncogene 27, 4255–4260 (2008). https://doi.org/10.1038/onc.2008.62

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Keywords

  • NMD
  • E-cadherin
  • CDH1
  • gastric cancer
  • HDGC
  • KATO-III

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