PTU-154 Sirt2 Modulates the Inflammatory Response in Oesophageal Adenocarcinoma

Abstract

Objective: Gastrooesophageal reflux disease (GORD) is the main risk factor for Barrett's oesophagus (BE), the precursor lesion to oesophageal adenocarcinoma (EAC). In BE, GORD leads to chronic inflammation and NFκB pathway activation. SIRT2 is a histone deacetylase involved in deacetylation of p65, one subunit of the NFκB complex. We hypothesised that SIRT2 recruits inflammatory cells to the tumour site via the NFκB pathway and aimed to assess the inflammatory infiltrate in SIRT2 positive tumours as well as the relationship between SIRT2 and the NFκB pathway. Methods: 76 surgical resection specimen of EAC were immunostained and double-scored for SIRT2 tumour and immune cell staining. An in-depth analysis of the nature of inflammatory cells localised to high SIRT2 areas was performed in 5 EAC cases using immune cell markers. NFκB luciferase reporter assays were used to study the interplay between the NFκB pathway and SIRT2. Results: 32% of the surgical cases were strongly positive for SIRT2 (+3 and +2 on a scale from 0 to +3 where 0 is negative).Ahigher number of inflammatory cells were identified in SIRT2- positive cases compared to SIRT2 negative cases. SIRT2 tumour staining was highly correlative with inflammation (pp = 2.2e-16). In particular, SIRT2 positive cases showed strong staining for CD68 indicating an enrichment in the number of macrophages. SIRT2 overexpression significantly downregulated NFκB activity (p = 0.0011). Immunoblotting suggests that this downregulation is probably conferred by the deacetylation of Lysine310 at the p65 subunit. Conclusion: In EAC, SIRT2 expression is linked with an increased inflammatory infiltrate, especially macrophages. Taken together, downregulation of NFκB by SIRT2 could be an explanation for the protective effect of SIRT2 overexpression in EAC.