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Downregulation of TRAIL-Receptor 1 Increases TGFβ Type II Receptor Expression and TGFβ Signalling Via MicroRNA-370-3p in Pancreatic Cancer Cells

The accumulation of perturbations in signalling pathways resulting in an apoptosis-insensitive phenotype is largely responsible for the desperate prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Accumulating evidence suggests that the death receptors TRAIL-R1 and TRAIL-R2 play imp...

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Autores principales: Radke, David I., Ling, Qi, Häsler, Robert, Alp, Gökhan, Ungefroren, Hendrik, Trauzold, Anna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267290/
https://www.ncbi.nlm.nih.gov/pubmed/30366420
http://dx.doi.org/10.3390/cancers10110399
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author Radke, David I.
Ling, Qi
Häsler, Robert
Alp, Gökhan
Ungefroren, Hendrik
Trauzold, Anna
author_facet Radke, David I.
Ling, Qi
Häsler, Robert
Alp, Gökhan
Ungefroren, Hendrik
Trauzold, Anna
author_sort Radke, David I.
collection PubMed
description The accumulation of perturbations in signalling pathways resulting in an apoptosis-insensitive phenotype is largely responsible for the desperate prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Accumulating evidence suggests that the death receptors TRAIL-R1 and TRAIL-R2 play important roles in PDAC biology by acting as either tumour suppressors through induction of cell death or tumour promoters through induction of pro-inflammatory signalling, invasion and metastasis. TRAIL-R2 can also associate with nuclear proteins and alter the maturation of micro RNAs (miRs). By genome-wide miR profiling and quantitative PCR analyses we now demonstrate that knockdown of TRAIL-R1 in PDAC cells decreased the level of mature miR-370 and led to an increased abundance of the type II receptor for transforming growth factor β (TGFβ). Transfection of cells with an artificial miR-370-3p decreased the levels of TGFβ-RII. We further show that transient expression of the miR-370 mimic decreased TGFβ1-induced expression of SERPINE1 encoding plasminogen activator-inhibitor 1 and partially relieved TGFβ1-induced growth inhibition. Moreover, stable TRAIL-R1 knockdown in Colo357 cells increased TGFβ1-induced SERPINE1 expression and this effect was partially reversed by transient expression of the miR-370 mimic. Finally, after transient knockdown of TRAIL-R1 in Panc1 cells there was a tendency towards enhanced activation of Smad2 and JNK1/2 signalling by exogenous TGFβ1. Taken together, our study reveals that TRAIL-R1 through regulation of miR-370 can decrease the sensitivity of PDAC cells to TGFβ and therefore represents a potential tumour suppressor in late-stage PDAC.
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spelling pubmed-62672902018-12-03 Downregulation of TRAIL-Receptor 1 Increases TGFβ Type II Receptor Expression and TGFβ Signalling Via MicroRNA-370-3p in Pancreatic Cancer Cells Radke, David I. Ling, Qi Häsler, Robert Alp, Gökhan Ungefroren, Hendrik Trauzold, Anna Cancers (Basel) Article The accumulation of perturbations in signalling pathways resulting in an apoptosis-insensitive phenotype is largely responsible for the desperate prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Accumulating evidence suggests that the death receptors TRAIL-R1 and TRAIL-R2 play important roles in PDAC biology by acting as either tumour suppressors through induction of cell death or tumour promoters through induction of pro-inflammatory signalling, invasion and metastasis. TRAIL-R2 can also associate with nuclear proteins and alter the maturation of micro RNAs (miRs). By genome-wide miR profiling and quantitative PCR analyses we now demonstrate that knockdown of TRAIL-R1 in PDAC cells decreased the level of mature miR-370 and led to an increased abundance of the type II receptor for transforming growth factor β (TGFβ). Transfection of cells with an artificial miR-370-3p decreased the levels of TGFβ-RII. We further show that transient expression of the miR-370 mimic decreased TGFβ1-induced expression of SERPINE1 encoding plasminogen activator-inhibitor 1 and partially relieved TGFβ1-induced growth inhibition. Moreover, stable TRAIL-R1 knockdown in Colo357 cells increased TGFβ1-induced SERPINE1 expression and this effect was partially reversed by transient expression of the miR-370 mimic. Finally, after transient knockdown of TRAIL-R1 in Panc1 cells there was a tendency towards enhanced activation of Smad2 and JNK1/2 signalling by exogenous TGFβ1. Taken together, our study reveals that TRAIL-R1 through regulation of miR-370 can decrease the sensitivity of PDAC cells to TGFβ and therefore represents a potential tumour suppressor in late-stage PDAC. MDPI 2018-10-25 /pmc/articles/PMC6267290/ /pubmed/30366420 http://dx.doi.org/10.3390/cancers10110399 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Radke, David I.
Ling, Qi
Häsler, Robert
Alp, Gökhan
Ungefroren, Hendrik
Trauzold, Anna
Downregulation of TRAIL-Receptor 1 Increases TGFβ Type II Receptor Expression and TGFβ Signalling Via MicroRNA-370-3p in Pancreatic Cancer Cells
title Downregulation of TRAIL-Receptor 1 Increases TGFβ Type II Receptor Expression and TGFβ Signalling Via MicroRNA-370-3p in Pancreatic Cancer Cells
title_full Downregulation of TRAIL-Receptor 1 Increases TGFβ Type II Receptor Expression and TGFβ Signalling Via MicroRNA-370-3p in Pancreatic Cancer Cells
title_fullStr Downregulation of TRAIL-Receptor 1 Increases TGFβ Type II Receptor Expression and TGFβ Signalling Via MicroRNA-370-3p in Pancreatic Cancer Cells
title_full_unstemmed Downregulation of TRAIL-Receptor 1 Increases TGFβ Type II Receptor Expression and TGFβ Signalling Via MicroRNA-370-3p in Pancreatic Cancer Cells
title_short Downregulation of TRAIL-Receptor 1 Increases TGFβ Type II Receptor Expression and TGFβ Signalling Via MicroRNA-370-3p in Pancreatic Cancer Cells
title_sort downregulation of trail-receptor 1 increases tgfβ type ii receptor expression and tgfβ signalling via microrna-370-3p in pancreatic cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267290/
https://www.ncbi.nlm.nih.gov/pubmed/30366420
http://dx.doi.org/10.3390/cancers10110399
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