Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet.
Acinar Cells
/ metabolism
Animals
Carcinoma, Pancreatic Ductal
/ genetics
Cell Transformation, Neoplastic
/ genetics
Diet, High-Fat
Down-Regulation
Fibroblast Growth Factors
/ genetics
Gene Expression Regulation, Neoplastic
Humans
Klotho Proteins
Membrane Proteins
/ genetics
Mice, Transgenic
Mutation
PPAR gamma
/ genetics
Pancreatic Cyst
/ genetics
Pancreatic Intraductal Neoplasms
/ genetics
Pancreatic Neoplasms
/ genetics
Pancreatitis
/ genetics
Proto-Oncogene Proteins p21(ras)
/ genetics
Receptor, Fibroblast Growth Factor, Type 1
/ genetics
Signal Transduction
Transcription Factors
/ genetics
Tumor Suppressor Protein p53
/ genetics
FGFR1
Gene Regulation
KLB
Signaling
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
13
11
2018
revised:
02
07
2019
accepted:
19
07
2019
pubmed:
29
7
2019
medline:
20
12
2019
entrez:
29
7
2019
Statut:
ppublish
Résumé
Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21, FGF21, a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis. We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 nontumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (Kras Pancreatic tissues of mice expressed high levels of FGF21 compared with liver tissues. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed Kras Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on an HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the guanosine triphosphate binding capacity of RAS. FGF21 might be used in the prevention or treatment of pancreatic cancer.
Sections du résumé
BACKGROUND & AIMS
Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21, FGF21, a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis.
METHODS
We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 nontumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (Kras
RESULTS
Pancreatic tissues of mice expressed high levels of FGF21 compared with liver tissues. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed Kras
CONCLUSIONS
Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on an HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the guanosine triphosphate binding capacity of RAS. FGF21 might be used in the prevention or treatment of pancreatic cancer.
Identifiants
pubmed: 31352001
pii: S0016-5085(19)41127-X
doi: 10.1053/j.gastro.2019.07.030
pmc: PMC6815712
mid: NIHMS1535715
pii:
doi:
Substances chimiques
KRAS protein, human
0
Klb protein, mouse
0
Membrane Proteins
0
PPAR gamma
0
Pparg protein, mouse
0
Transcription Factors
0
Trp53 protein, mouse
0
Tumor Suppressor Protein p53
0
fibroblast growth factor 21
0
transcription factor PTF1
0
Fibroblast Growth Factors
62031-54-3
Fgfr1 protein, mouse
EC 2.7.10.1
Receptor, Fibroblast Growth Factor, Type 1
EC 2.7.10.1
Klotho Proteins
EC 3.2.1.31
Hras protein, mouse
EC 3.6.5.2
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
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
1413-1428.e11Subventions
Organisme : NCI NIH HHS
ID : P20 CA192996
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : P20 CA192994
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK052067
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA045508
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014236
Pays : United States
Informations de copyright
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
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