Loss of HIF1A From Pancreatic Cancer Cells Increases Expression of PPP1R1B and Degradation of p53 to Promote Invasion and Metastasis.

Autor:	Tiwari A; Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. Electronic address: atiwari@sbpdiscovery.org., Tashiro K; Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California., Dixit A; Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota., Soni A; Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California., Vogel K; Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California., Hall B; Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California., Shafqat I; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota., Slaughter J; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota., Param N; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota., Le A; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota., Saunders E; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota., Paithane U; Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California., Garcia G; Histology Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California., Campos AR; Proteomics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California., Zettervall J; Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota., Carlson M; Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota., Starr TK; Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota., Marahrens Y; Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota., Deshpande AJ; Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California., Commisso C; Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California., Provenzano PP; Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota., Bagchi A; Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. Electronic address: abagchi@sbpdiscovery.org.
Jazyk:	angličtina
Zdroj:	Gastroenterology [Gastroenterology] 2020 Nov; Vol. 159 (5), pp. 1882-1897.e5. Date of Electronic Publication: 2020 Aug 05.
DOI:	10.1053/j.gastro.2020.07.046
Abstrakt:	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 LSL-G12D/+ ;Trp53 LSL-R172H/+ ;Pdx1-Cre (KPC) mice, KPC mice with labeled pancreatic epithelial cells (EKPC), and EKPC mice with pancreas-specific depletion of HIF1A. Pancreatic and other tissues were collected and analyzed by histology and immunohistochemistry. Cancer cells were cultured from PDACs from mice and analyzed in cell migration and invasion assays and by immunoblots, real-time polymerase chain reaction, and liquid chromatography-mass spectrometry. We performed studies with the human pancreatic cancer cell lines PATU-8988T, BxPC-3, PANC-1, and MiaPACA-2, which have no or low metastatic activity, and PATU-8988S, AsPC-1, SUIT-2 and Capan-1, which have high metastatic activity. Expression of genes was knocked down in primary cancer cells and pancreatic cancer cell lines by using small hairpin RNAs; cells were injected intravenously into immune-competent and NOD/SCID mice, and lung metastases were quantified. We compared levels of messenger RNAs in pancreatic tumors and normal pancreas in The Cancer Genome Atlas. 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. (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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