Loss of HIF1A From Pancreatic Cancer Cells Increases Expression of PPP1R1B and Degradation of p53 to Promote Invasion and Metastasis.
Animals
Carcinoma, Pancreatic Ductal
/ genetics
Cell Line, Tumor
Cell Movement
Disease Models, Animal
Dopamine and cAMP-Regulated Phosphoprotein 32
/ genetics
Epithelial-Mesenchymal Transition
Female
Gene Expression Regulation, Neoplastic
Homeodomain Proteins
/ genetics
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
/ deficiency
Lung Neoplasms
/ genetics
Male
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Neoplasm Invasiveness
Pancreatic Neoplasms
/ genetics
Proteolysis
Proto-Oncogene Proteins p21(ras)
/ genetics
Signal Transduction
Trans-Activators
/ genetics
Tumor Hypoxia
Tumor Microenvironment
Tumor Suppressor Protein p53
/ genetics
Up-Regulation
Carcinogenesis
Cell Motility
Signal Transduction
Tumor Progression
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
14
11
2019
revised:
11
07
2020
accepted:
27
07
2020
pubmed:
10
8
2020
medline:
13
4
2021
entrez:
10
8
2020
Statut:
ppublish
Résumé
Pancreatic ductal adenocarcinomas (PDACs) are hypovascular, resulting in the up-regulation of hypoxia inducible factor 1 alpha (HIF1A), which promotes the survival of cells under low-oxygen conditions. We studied the roles of HIF1A in the development of pancreatic tumors in mice. We performed studies with Kras EKPC mice with pancreas-specific deletion of HIF1A developed more advanced pancreatic neoplasias and PDACs with more invasion and metastasis, and had significantly shorter survival times, than EKPC mice. Pancreatic cancer cells from these tumors had higher invasive and metastatic activity in culture than cells from tumors of EKPC mice. HIF1A-knockout pancreatic cancer cells had increased expression of protein phosphatase 1 regulatory inhibitor subunit 1B (PPP1R1B). There was an inverse correlation between levels of HIF1A and PPP1R1B in human PDAC tumors; higher expression of PPP1R1B correlated with shorter survival times of patients. Metastatic human pancreatic cancer cell lines had increased levels of PPP1R1B and lower levels of HIF1A compared with nonmetastatic cancer cell lines; knockdown of PPP1R1B significantly reduced the ability of pancreatic cancer cells to form lung metastases in mice. PPP1R1B promoted degradation of p53 by stabilizing phosphorylation of MDM2 at Ser166. HIF1A can act a tumor suppressor by preventing the expression of PPP1R1B and subsequent degradation of the p53 protein in pancreatic cancer cells. Loss of HIF1A from pancreatic cancer cells increases their invasive and metastatic activity.
Sections du résumé
BACKGROUND & AIMS
Pancreatic ductal adenocarcinomas (PDACs) are hypovascular, resulting in the up-regulation of hypoxia inducible factor 1 alpha (HIF1A), which promotes the survival of cells under low-oxygen conditions. We studied the roles of HIF1A in the development of pancreatic tumors in mice.
METHODS
We performed studies with Kras
RESULTS
EKPC mice with pancreas-specific deletion of HIF1A developed more advanced pancreatic neoplasias and PDACs with more invasion and metastasis, and had significantly shorter survival times, than EKPC mice. Pancreatic cancer cells from these tumors had higher invasive and metastatic activity in culture than cells from tumors of EKPC mice. HIF1A-knockout pancreatic cancer cells had increased expression of protein phosphatase 1 regulatory inhibitor subunit 1B (PPP1R1B). There was an inverse correlation between levels of HIF1A and PPP1R1B in human PDAC tumors; higher expression of PPP1R1B correlated with shorter survival times of patients. Metastatic human pancreatic cancer cell lines had increased levels of PPP1R1B and lower levels of HIF1A compared with nonmetastatic cancer cell lines; knockdown of PPP1R1B significantly reduced the ability of pancreatic cancer cells to form lung metastases in mice. PPP1R1B promoted degradation of p53 by stabilizing phosphorylation of MDM2 at Ser166.
CONCLUSIONS
HIF1A can act a tumor suppressor by preventing the expression of PPP1R1B and subsequent degradation of the p53 protein in pancreatic cancer cells. Loss of HIF1A from pancreatic cancer cells increases their invasive and metastatic activity.
Identifiants
pubmed: 32768595
pii: S0016-5085(20)35009-5
doi: 10.1053/j.gastro.2020.07.046
pmc: PMC7680408
mid: NIHMS1618842
pii:
doi:
Substances chimiques
Dopamine and cAMP-Regulated Phosphoprotein 32
0
HIF1A protein, human
0
Hif1a protein, mouse
0
Homeodomain Proteins
0
Hypoxia-Inducible Factor 1, alpha Subunit
0
PPP1R1B protein, human
0
Ppp1r1b protein, mouse
0
TP53 protein, human
0
Trans-Activators
0
Trp53 protein, mouse
0
Tumor Suppressor Protein p53
0
pancreatic and duodenal homeobox 1 protein
0
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
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1882-1897.e5Subventions
Organisme : NCI NIH HHS
ID : R01 CA207189
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA200643
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA030199
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA181385
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA210190
Pays : United States
Informations de copyright
Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.