ORIGINAL ARTICLE

MUC4 is increased in high grade intraepithelial neoplasia in Barrett’s oesophagus and is associated with a proapoptotic Bax to Bcl-2 ratio

D A Bax¹, J Haringsma¹, A W C Einerhand², H van Dekken³, P Blok⁴, P D Siersema¹, E J Kuipers¹, J G Kusters¹

¹ Department of Gastroenterology and Hepatology, Erasmus MC – University Medical Centre, 3015 GD Rotterdam, The Netherlands
² Laboratory of Paediatrics, Erasmus MC – Sophia Children’s Hospital, Rotterdam, The Netherlands
³ Department of Pathology, Erasmus MC – University Medical Centre, Rotterdam, The Netherlands
⁴ Department of Pathology, Leyenburg Ziekenhuis, The Hague, The Netherlands

Correspondence to:
Correspondence to:
Dr J G Kusters
Erasmus MC, University Medical Centre Rotterdam, Department of Gastroenterology and Hepatology, Room L-459, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands; j.g.kusters{at}erasmusmc.nl

Background: Patients with Barrett’s oesophagus (BO) are at risk of oesophageal adenocarcinoma. Because the pattern of mucosal mucins changes during neoplastic progression, it may serve as a marker of intraepithelial neoplasia.

Aims: To determine the expression pattern of mucins in neoplastic BO epithelium (high grade dysplasia) and correlate it with the expression of apoptosis markers Bax and Bcl-2.

Methods: Thirty seven patients with BO were studied: 16 without intraepithelial neoplasia, six with high grade intraepithelial neoplasia (HGN), and 15 with infiltrating adenocarcinoma. Biopsies were obtained from squamous epithelium, Barrett’s epithelium, and (when present) foci of suspected HGN or adenocarcinoma. MUC1–4, MUC5AC, MUC5B, MUC6, Bax, and Bcl-2 mRNA were determined by semiquantitative RT-PCR. MUC2, MUC5AC, and MUC6 protein was determined by immunoblotting.

Results: Mucin expression varied between neoplastic progression stages in BO. Mucin mRNA levels were low in squamous epithelium, except for MUC4, and were at least four times higher in BO and HGN (p<0.001), but less so in adenocarcinoma. MUC4 expression was significantly lower in BO than in normal squamous epithelium, whereas in HGN and adenocarcinoma, levels were significantly higher than in BO (p = 0.037). The Bax:Bcl-2 ratio was increased in HGN compared with BO (p = 0.04). MUC2, MUC5AC, and MUC6 protein values correlated with mRNA data.

Conclusions: Mucin expression varies during the development of oesophageal adenocarcinoma in BO. MUC4 could serve as a tumour marker in this process. In contrast to animal studies, upregulation of MUC4 in HGN is associated with increased apoptosis, suggesting that MUC4 plays a minor role in apoptosis regulation in BO.

Abbreviations: ADC, adenocarcinoma; AP, alkaline phosphatase; BO, Barrett’s oesophagus; HGN, high grade intraepithelial neoplasia; PCR, polymerase chain reaction; RT, reverse transcription

Keywords: Barrett’s oesophagus; high grade dysplasia; mucins; apoptosis; tumour markers

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