Splicing Factor SRSF1 Promotes Pancreatitis and KRASG12D-Mediated Pancreatic Cancer.
Animals
Mice
Alternative Splicing
Carcinogenesis
/ genetics
Carcinoma, Pancreatic Ductal
/ pathology
Cell Transformation, Neoplastic
/ genetics
Inflammation
Pancreatic Neoplasms
/ pathology
Pancreatitis
/ genetics
RNA Splicing Factors
/ genetics
Serine-Arginine Splicing Factors
/ genetics
Humans
Pancreatic Neoplasms
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
07 07 2023
07 07 2023
Historique:
received:
09
09
2022
revised:
14
02
2023
accepted:
22
03
2023
pmc-release:
07
01
2024
medline:
10
7
2023
pubmed:
26
4
2023
entrez:
26
4
2023
Statut:
ppublish
Résumé
Inflammation is strongly associated with pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy. Dysregulated RNA splicing factors have been widely reported in tumorigenesis, but their involvement in pancreatitis and PDAC is not well understood. Here, we report that the splicing factor SRSF1 is highly expressed in pancreatitis, PDAC precursor lesions, and tumors. Increased SRSF1 is sufficient to induce pancreatitis and accelerate KRASG12D-mediated PDAC. Mechanistically, SRSF1 activates MAPK signaling-partly by upregulating interleukin 1 receptor type 1 (IL1R1) through alternative-splicing-regulated mRNA stability. Additionally, SRSF1 protein is destabilized through a negative feedback mechanism in phenotypically normal epithelial cells expressing KRASG12D in mouse pancreas and in pancreas organoids acutely expressing KRASG12D, buffering MAPK signaling and maintaining pancreas cell homeostasis. This negative feedback regulation of SRSF1 is overcome by hyperactive MYC, facilitating PDAC tumorigenesis. Our findings implicate SRSF1 in the etiology of pancreatitis and PDAC, and point to SRSF1-misregulated alternative splicing as a potential therapeutic target. We describe the regulation of splicing factor SRSF1 expression in the context of pancreas cell identity, plasticity, and inflammation. SRSF1 protein downregulation is involved in a negative feedback cellular response to KRASG12D expression, contributing to pancreas cell homeostasis. Conversely, upregulated SRSF1 promotes pancreatitis and accelerates KRASG12D-mediated tumorigenesis through enhanced IL1 and MAPK signaling. This article is highlighted in the In This Issue feature, p. 1501.
Identifiants
pubmed: 37098965
pii: 725938
doi: 10.1158/2159-8290.CD-22-1013
pmc: PMC10330071
mid: NIHMS1888389
doi:
Substances chimiques
RNA Splicing Factors
0
Serine-Arginine Splicing Factors
170974-22-8
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1678-1695Subventions
Organisme : NCI NIH HHS
ID : R01 CA249002
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211506
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA045508
Pays : United States
Organisme : NIH HHS
ID : S10 OD028632
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA013106
Pays : United States
Informations de copyright
©2023 American Association for Cancer Research.
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