1. O papel dos C/EBPs no estômago. Diferenciação vs proliferação. José Carlos Machado, Porto, Portugal

2. Aneuploidy # 3p, 7q, 13q (LOH) # 6q (LOH) # 1q, 5q, 17p (LOH) RAS (overexpression/mutation) ERBB-2 (amplification) TPR-MET (rearrangement) c-MET (6.0 Kb mARN) p 53 (LOH, mutation) APC (LOH, mutation) DCC (LOH) EGF (overexpression) TGF-a (overexpression) TFF1 (loss of expression) MSI (Microsatellite Instability) S-Tn, T, S-T CDw75, S-Lex Laminin, collagen IV u-PA, Cat-D NM 23 (loss) CD 44 (variants) Diploidy # 3p, 7q, 13q (LOH) # 6q (LOH) c-MET (6.0 Kb mRNA) p 53 (LOH, mutation) TGF-ß (overexpression) K-SAM (amplification) E-cadherin (loss/mutation) S-Tn, T, S-T CDw75, S-Lex NM 23 (loss) CD 44 (variants) Intestinal carcinoma Diffuse carcinoma

3. Gastric gland

4. TFF1 expression in gastric carcinogenesis. Machado JC et al. J Pathol 190: 437, 2000

5. C/EBPbeta Ki67 Ki67 and C/EBP-β in normal gastric mucosa

6. Intestinal metaplasiaGastric dysplasia C/EBPbeta expression

7. Intestinalatypicaldiffuse IntestinalSolid Diffuse C/EBPbeta expression

8. C/EBP-β staining overlaps Ki67 C/EBPKi67

9. C/EBPbeta mutation in a primary gastric carcinoma Pro58Ala Wild-type

10. Basic leucine zipper DNA-binding protein C/EBP-β or NFIL6

11. TFF1 knockout mice developed adenomas and gastric cancer Lefebvre O et al. Science 274: 259, 1996

12. C/EBPbeta and COX-2 co-expression in gastric carcinoma COX2C/EBPbetaDouble IHC

13. C/EBP-β expression in GC cell lines

14. Luciferase assay showing the effect of C/EBPbeta transfection on COX-2 promoter activity

15. C/EBPα is expressed in gastric differentiated cells and co-localizes with TFF1

16. C/EBPα is under expressed in 34.6% of intestinal and atypical but not diffuse type carcinomas non-neoplasticintestinaldiffuse

17. A C/EBPα expression vector inhibits AGS cell proliferation BRDU Dapi média 0 5 10 15 20 25 30 35 40 45 Mock42KD isoformas % proliferação média

18. C/EBPα modulates cell cycle proteins and is capable of up-regulating TFF1 expression

19. EGFR HER2/neu IL6R/GP130 TGFBR STAT3 Pi3K Ras SHP2 GSK3beta ERK C/EBPbeta Smad3 phosphorylation inactivation AKT TFF1 COX2 Candidate signalling pathways

20. C/EBPβ C/EBPα ciclinD1 p-ERK1/2 p-p38 tubulin C/EBP  stimulation with IL1B leads to phosphoeilation of ERK1/2 and p38 0 SBPD IL1b IL1b+ SB- p38 IL1b+ PD ERK

21. phospho-p38 C/EBP β Ki67 C/EBP  co-localizes with phopho-p38

22. Conclusions C/EBPbeta is expressed in proliferative cells of the normal gastric mucosa, and is overexpressed in intestinal metaplasia, dysplasia, and GC of the intestinal and atypical subtypes; COX-2 is co-expressed with C/EBPbeta and can be regulated by this transcription factor; C/EBPbeta may both be a marker of neoplastic transformation and play an active role in gastric tumourigenesis by regulating COX-2 expression; C/EBPα is expressed in gastric foveolar differentiated cells and under-expressed in intestinal and atypical type tumours; C/EBPα colocalizes with and up-regulates TFF1, and inhibits cell proliferation by changing the expression of cell cycle proteins in vitro.