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Programmed cell death 4 (PDCD4) expression during multistep Barrett's carcinogenesis.

ABSTRACT: AIM: To test the contribution of programmed cell death 4 (PDCD4) tumour suppressor gene in Barrett's carcinogenesis. METHODS: PDCD4 immunohistochemical expression was assessed in 88 biopsy samples obtained from histologically proven long-segment Barrett's mucosa (BM; 25 non-intestinal columnar metaplasia, 25 intestinal metaplasia (IM), 16 low-grade intraepithelial neoplasia (LG-IEN), 12 high-grade IEN (HG-IEN) and 10 Barrett's adenocarcinoma (BAc)). As controls, 25 additional samples of native oesophageal mucosa (N) were obtained from patients with dyspepsia. To further support the data, the expression levels of miR-21, an important PDCD4 expression regulator, in 14 N, 5 HG-IEN and 11 BAc samples were determined by quantitative real-time PCR analysis. Results PDCD4 immunostaining decreased progressively and significantly with the progression of the phenotypic changes occurring during Barrett's carcinogenesis (p<0.001). Normal basal squamous epithelial layers featured strong PDCD4 nuclear immunoreaction (mostly coexisting with weak-moderate cytoplasmic staining). Non-intestinal columnar metaplasia and intestinal metaplasia preserved a strong nuclear immunostaining; conversely, a significant decrease in PDCD4 nuclear expression was seen in dysplastic (LG-IEN and HG-IEN) and neoplastic lesions. Weak-moderate cytoplasmic immunostaining was evident in cases of LG-IEN, while HG-IEN and BAc samples showed weak cytoplasmic or no protein expression. As expected, miR-21 expression was significantly upregulated in HG-IEN and BAc samples, consistently with PDCD4 dysregulation. CONCLUSIONS: These data support a significant role for PDCD4 downregulation in the progression of BM to BAc, and confirm miR-21 as a negative regulator of PDCD4 in vivo. Further efforts are needed to validate PDCD4 as a potential prognostic marker in patients with Barrett's oesophagus.

SUBMITTER: Fassan M

PROVIDER: S-EPMC2976066 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Programmed cell death 4 (PDCD4) expression during multistep Barrett's carcinogenesis.

Fassan Matteo M Pizzi Marco M Battaglia Giorgio G Giacomelli Luciano L Parente Paola P Bocus Paolo P Ancona Ermanno E Rugge Massimo M

Journal of clinical pathology 20100801 8

<h4>Aim</h4>To test the contribution of programmed cell death 4 (PDCD4) tumour suppressor gene in Barrett's carcinogenesis.<h4>Methods</h4>PDCD4 immunohistochemical expression was assessed in 88 biopsy samples obtained from histologically proven long-segment Barrett's mucosa (BM; 25 non-intestinal columnar metaplasia, 25 intestinal metaplasia (IM), 16 low-grade intraepithelial neoplasia (LG-IEN), 12 high-grade IEN (HG-IEN) and 10 Barrett's adenocarcinoma (BAc)). As controls, 25 additional sample ...[more]

PMID: 20702469

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Project description:Background:The primary goal of papillary thyroid cancer (PTC) management was to stratify patients at pre- and post-surgical level to identify the small proportion of cases with potentially aggressive disease. Purpose:The aim of our study is to evaluate the possible role of programmed cell death 4 (PDCD4) and BRAF status as prognostic markers in PTC. Patients and methods:We investigate programmed cell death 4 (PDCD4) immunohistochemical expression in 125 consecutive PTCs with median follow-up of 75.3 months (range, 15-98 months) to verify the possible correlation between BRAF status and correlate the classical clinicopathological prognostic factors and PTC outcome with PDCD4 expression. To further support the data, miR-21 expression was tested (by quantitative real-time PCR and in situ hybridization) in a different series of 30 cases (15 PTCs BRAFwt and 15 PTCs BRAFV600E). Moreover, we validated our results using TGCA thyroid carcinoma dataset. Results:We found that 59.8% of the patients showed low-grade PDCD4 nuclear expression and low-grade expression correlated with BRAF V600E. Compared with BRAF 15 wild-type tissue samples, a significant miR-21 up-regulation was associated with BRAF V600E mutations. Low-grade PDCD4 resulted, and was associated with aggressive histological variants, higher cancer size, extra-thyroidal extension, multifocality, lymph-node metastasis and lymph nodal ratio at the diagnosis. Concerning the outcome, the low-grade PDCD4 expression correlated at univariate and multivariate analysis, with lower levels of recurrence-free survival rate (RFS) and with poor outcome. Moreover, there was significant association between BRAF V600E patients with PDCD4 nuclear loss and lower RFS, whilet here was significant association between BRAF wild-type patients with PDCD4 nuclear expression and better outcome. Conclusion:These results showed that PDCD4 could predict PTC outcome and that the sum of PDCD4 and BRAF alterations increases the prognostic power of BRAF mutation alone.

Dataset Information

Programmed cell death 4 (PDCD4) expression during multistep Barrett's carcinogenesis.

Publications

Programmed cell death 4 (PDCD4) expression during multistep Barrett's carcinogenesis.

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