SMAD2/3 mediate oncogenic effects of TGF-β in the absence of SMAD4.
Carcinogenesis
/ genetics
Carcinoma, Pancreatic Ductal
/ metabolism
Humans
Pancreatic Neoplasms
/ metabolism
RNA
Smad2 Protein
/ genetics
Smad3 Protein
/ metabolism
Smad4 Protein
/ genetics
Transforming Growth Factor beta
/ pharmacology
Transforming Growth Factor beta1
/ metabolism
Pancreatic Neoplasms
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
07 10 2022
07 10 2022
Historique:
received:
03
09
2021
accepted:
14
09
2022
entrez:
7
10
2022
pubmed:
8
10
2022
medline:
12
10
2022
Statut:
epublish
Résumé
TGF-β signaling is involved in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis, representing one of the four major pathways genetically altered in 100% of PDAC cases. TGF-β exerts complex and pleiotropic effects in cancers, notably via the activation of SMAD pathways, predominantly SMAD2/3/4. Though SMAD2 and 3 are rarely mutated in cancers, SMAD4 is lost in about 50% of PDAC, and the role of SMAD2/3 in a SMAD4-null context remains understudied. We herein provide evidence of a SMAD2/3 oncogenic effect in response to TGF-β1 in SMAD4-null human PDAC cancer cells. We report that inactivation of SMAD2/3 in SMAD4-negative PDAC cells compromises TGF-β-driven collective migration mediated by FAK and Rho/Rac signaling. Moreover, RNA-sequencing analyses highlight a TGF-β gene signature related to aggressiveness mediated by SMAD2/3 in the absence of SMAD4. Using a PDAC patient cohort, we reveal that SMAD4-negative tumors with high levels of phospho-SMAD2 are more aggressive and have a poorer prognosis. Thus, loss of SMAD4 tumor suppressive activity in PDAC leads to an oncogenic gain-of-function of SMAD2/3, and to the onset of associated deleterious effects.
Identifiants
pubmed: 36207615
doi: 10.1038/s42003-022-03994-6
pii: 10.1038/s42003-022-03994-6
pmc: PMC9546935
doi:
Substances chimiques
SMAD2 protein, human
0
SMAD3 protein, human
0
SMAD4 protein, human
0
Smad2 Protein
0
Smad3 Protein
0
Smad4 Protein
0
Transforming Growth Factor beta
0
Transforming Growth Factor beta1
0
RNA
63231-63-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1068Informations de copyright
© 2022. The Author(s).
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