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O papel dos C/EBPs no estômago. Diferenciação vs proliferação.

O papel dos C/EBPs no estômago. Diferenciação vs proliferação. José Carlos Machado, Porto, Portugal. Intestinal carcinoma Diffuse carcinoma. Aneuploidy # 3p, 7q, 13q (LOH) # 6q (LOH) # 1q, 5q, 17p (LOH) RAS (overexpression/mutation) ERBB-2 (amplification)

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O papel dos C/EBPs no estômago. Diferenciação vs proliferação.

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

  2. Intestinal carcinoma Diffuse carcinoma 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)

  3. Gastric gland

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

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

  6. C/EBPbeta expression Intestinal metaplasia Gastric dysplasia

  7. C/EBPbeta expression Intestinal atypical diffuse Intestinal Solid Diffuse

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

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

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

  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 COX2 C/EBPbeta Double 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-neoplastic intestinal diffuse

  17. média 45 40 35 30 25 média % proliferação 20 15 10 5 0 Mock 42KD isoformas A C/EBPα expression vector inhibits AGS cell proliferation BRDU Dapi

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

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

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

  21. C/EBPb co-localizes with phopho-p38 C/EBPβ phospho-p38 Ki67

  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.

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