1 / 22

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)

loc
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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.

More Related