Diabetes in Humans Activates Pancreatic Stellate Cells via RAGE in Pancreatic Ductal Adenocarcinoma

Pancreatic stellate cells (PSCs) mainly consist of cancer-associating fibroblasts in pancreatic ductal adenocarcinoma (PDAC). The receptor for advanced glycation end products (RAGE) is implicated in the pathophysiology of diabetic complications. Here, we studied the implication of RAGE in PSC activa...

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Autores principales:	Chiaki Uchida, Hiroki Mizukami, Yutaro Hara, Takeshi Saito, Satoko Umetsu, Akiko Igawa, Sho Osonoi, Kazuhiro Kudoh, Yasuhiko Yamamoto, Hiroshi Yamamoto, Soroku Yagihashi, Kenichi Hakamada
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	type 2 diabetes advanced glycation end products pancreatic ductal adenocarcinoma RAGE EMT metabolic syndrome Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/17044c4b692544f5832864a0407f0f4f
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spelling	oai:doaj.org-article:17044c4b692544f5832864a0407f0f4f2021-11-11T17:10:25ZDiabetes in Humans Activates Pancreatic Stellate Cells via RAGE in Pancreatic Ductal Adenocarcinoma10.3390/ijms2221117161422-00671661-6596https://doaj.org/article/17044c4b692544f5832864a0407f0f4f2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11716https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Pancreatic stellate cells (PSCs) mainly consist of cancer-associating fibroblasts in pancreatic ductal adenocarcinoma (PDAC). The receptor for advanced glycation end products (RAGE) is implicated in the pathophysiology of diabetic complications. Here, we studied the implication of RAGE in PSC activation in PDAC. The activation of cultured mouse PSCs was evaluated by qPCR. The induction of epithelial mesenchymal transition (EMT) in PDAC cell lines was assessed under stimulation with culture supernatant from activated PSCs. A total of 155 surgically resected PDAC subjects (83 nondiabetic, 18 with ≦3-years and 54 with >3-years history of diabetes) were clinicopathologically evaluated. A high-fat diet increased the expression of activated markers in cultured PSCs, which was abrogated by RAGE deletion. Culture supernatant from activated PSCs facilitated EMT of PDAC cells with elevation of TGF−β and IL−6, but not from RAGE−deleted PSCs. Diabetic subjects complicated with metabolic syndrome, divided by cluster analysis, showed higher PSC activation and RAGE expression. In such groups, PDAC cells exhibited an EMT nature. The complication of metabolic syndrome with diabetes significantly worsened disease−free survival of PDAC subjects. Thus, RAGE in PSCs can be viewed as a new promoter and a future therapeutic target of PDAC in diabetic subjects with metabolic syndrome.Chiaki UchidaHiroki MizukamiYutaro HaraTakeshi SaitoSatoko UmetsuAkiko IgawaSho OsonoiKazuhiro KudohYasuhiko YamamotoHiroshi YamamotoSoroku YagihashiKenichi HakamadaMDPI AGarticletype 2 diabetesadvanced glycation end productspancreatic ductal adenocarcinomaRAGEEMTmetabolic syndromeBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11716, p 11716 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	type 2 diabetes advanced glycation end products pancreatic ductal adenocarcinoma RAGE EMT metabolic syndrome Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	type 2 diabetes advanced glycation end products pancreatic ductal adenocarcinoma RAGE EMT metabolic syndrome Biology (General) QH301-705.5 Chemistry QD1-999 Chiaki Uchida Hiroki Mizukami Yutaro Hara Takeshi Saito Satoko Umetsu Akiko Igawa Sho Osonoi Kazuhiro Kudoh Yasuhiko Yamamoto Hiroshi Yamamoto Soroku Yagihashi Kenichi Hakamada Diabetes in Humans Activates Pancreatic Stellate Cells via RAGE in Pancreatic Ductal Adenocarcinoma
description	Pancreatic stellate cells (PSCs) mainly consist of cancer-associating fibroblasts in pancreatic ductal adenocarcinoma (PDAC). The receptor for advanced glycation end products (RAGE) is implicated in the pathophysiology of diabetic complications. Here, we studied the implication of RAGE in PSC activation in PDAC. The activation of cultured mouse PSCs was evaluated by qPCR. The induction of epithelial mesenchymal transition (EMT) in PDAC cell lines was assessed under stimulation with culture supernatant from activated PSCs. A total of 155 surgically resected PDAC subjects (83 nondiabetic, 18 with ≦3-years and 54 with >3-years history of diabetes) were clinicopathologically evaluated. A high-fat diet increased the expression of activated markers in cultured PSCs, which was abrogated by RAGE deletion. Culture supernatant from activated PSCs facilitated EMT of PDAC cells with elevation of TGF−β and IL−6, but not from RAGE−deleted PSCs. Diabetic subjects complicated with metabolic syndrome, divided by cluster analysis, showed higher PSC activation and RAGE expression. In such groups, PDAC cells exhibited an EMT nature. The complication of metabolic syndrome with diabetes significantly worsened disease−free survival of PDAC subjects. Thus, RAGE in PSCs can be viewed as a new promoter and a future therapeutic target of PDAC in diabetic subjects with metabolic syndrome.
format	article
author	Chiaki Uchida Hiroki Mizukami Yutaro Hara Takeshi Saito Satoko Umetsu Akiko Igawa Sho Osonoi Kazuhiro Kudoh Yasuhiko Yamamoto Hiroshi Yamamoto Soroku Yagihashi Kenichi Hakamada
author_facet	Chiaki Uchida Hiroki Mizukami Yutaro Hara Takeshi Saito Satoko Umetsu Akiko Igawa Sho Osonoi Kazuhiro Kudoh Yasuhiko Yamamoto Hiroshi Yamamoto Soroku Yagihashi Kenichi Hakamada
author_sort	Chiaki Uchida
title	Diabetes in Humans Activates Pancreatic Stellate Cells via RAGE in Pancreatic Ductal Adenocarcinoma
title_short	Diabetes in Humans Activates Pancreatic Stellate Cells via RAGE in Pancreatic Ductal Adenocarcinoma
title_full	Diabetes in Humans Activates Pancreatic Stellate Cells via RAGE in Pancreatic Ductal Adenocarcinoma
title_fullStr	Diabetes in Humans Activates Pancreatic Stellate Cells via RAGE in Pancreatic Ductal Adenocarcinoma
title_full_unstemmed	Diabetes in Humans Activates Pancreatic Stellate Cells via RAGE in Pancreatic Ductal Adenocarcinoma
title_sort	diabetes in humans activates pancreatic stellate cells via rage in pancreatic ductal adenocarcinoma
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/17044c4b692544f5832864a0407f0f4f
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Diabetes in Humans Activates Pancreatic Stellate Cells via RAGE in Pancreatic Ductal Adenocarcinoma

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