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Increased expression of PHD3 represses the HIF-1 signaling pathway and contributes to poor neovascularization in pancreatic ductal adenocarcinoma

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is known as one of the most malignant potential diseases with poor neovascularization. By comparing PDAC to hepatocellular carcinoma (HCC), which is well vascularized, we investigated the mechanisms and tumor biological significance of the poor neo...

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Autores principales: Tanaka, Takayuki, Li, Tao-Sheng, Urata, Yoshishige, Goto, Shinji, Ono, Yusuke, Kawakatsu, Miho, Matsushima, Hajime, Hirabaru, Masataka, Adachi, Tomohiko, Kitasato, Amane, Takatsuki, Mitsuhisa, Kuroki, Tamotsu, Eguchi, Susumu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Japan 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561234/
https://www.ncbi.nlm.nih.gov/pubmed/25542265
http://dx.doi.org/10.1007/s00535-014-1030-3
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author Tanaka, Takayuki
Li, Tao-Sheng
Urata, Yoshishige
Goto, Shinji
Ono, Yusuke
Kawakatsu, Miho
Matsushima, Hajime
Hirabaru, Masataka
Adachi, Tomohiko
Kitasato, Amane
Takatsuki, Mitsuhisa
Kuroki, Tamotsu
Eguchi, Susumu
author_facet Tanaka, Takayuki
Li, Tao-Sheng
Urata, Yoshishige
Goto, Shinji
Ono, Yusuke
Kawakatsu, Miho
Matsushima, Hajime
Hirabaru, Masataka
Adachi, Tomohiko
Kitasato, Amane
Takatsuki, Mitsuhisa
Kuroki, Tamotsu
Eguchi, Susumu
author_sort Tanaka, Takayuki
collection PubMed
description BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is known as one of the most malignant potential diseases with poor neovascularization. By comparing PDAC to hepatocellular carcinoma (HCC), which is well vascularized, we investigated the mechanisms and tumor biological significance of the poor neovascularization in PDAC. METHODS: Surgical specimens from primary PDAC and HCC patients were immunohistologically stained to detect the expressions of CD105, CD44, HIF-1α, PHD3, and Siah2. We also used two PDAC and two HCC cell lines to compare the expressions of HIF-1α, PHD3, and CD44, as well as the production of VEGF in hypoxic condition. The role of PHD3 in regulating HIF-1α expression was further confirmed by siRNA knockdown in a PDAC cell line that highly expressed PHD3. RESULTS: There were significantly fewer microvessels but more cancer stem cells in PDAC specimens compared to HCC specimens. The expression of CD105 was reversely related to the expression of CD44 in PDAC and HCC specimens. PDAC specimens also showed higher expressions of PHD3 but lower expressions of HIF-1α. Similarly, the expression of PHD3 was observed clearly in PDAC cell lines, but was almost completely negative in HCC cell lines. Hypoxic stimulation clearly enhanced HIF-1α expression and VEGF secretion in both HCC cell lines, but did not significantly change in PDAC cell lines. The knockdown of PHD3 in PDAC cells restored the hypoxic-induced HIF-1α expression, which accordingly stimulated the cells’ VEGF secretion. CONCLUSIONS: The enhanced expression of PHD3 might likely contribute to the poor neovascularization and affect the biological characterization in PDAC cancer cells.
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spelling pubmed-45612342015-09-11 Increased expression of PHD3 represses the HIF-1 signaling pathway and contributes to poor neovascularization in pancreatic ductal adenocarcinoma Tanaka, Takayuki Li, Tao-Sheng Urata, Yoshishige Goto, Shinji Ono, Yusuke Kawakatsu, Miho Matsushima, Hajime Hirabaru, Masataka Adachi, Tomohiko Kitasato, Amane Takatsuki, Mitsuhisa Kuroki, Tamotsu Eguchi, Susumu J Gastroenterol Original Article—Liver, Pancreas, and Biliary Tract BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is known as one of the most malignant potential diseases with poor neovascularization. By comparing PDAC to hepatocellular carcinoma (HCC), which is well vascularized, we investigated the mechanisms and tumor biological significance of the poor neovascularization in PDAC. METHODS: Surgical specimens from primary PDAC and HCC patients were immunohistologically stained to detect the expressions of CD105, CD44, HIF-1α, PHD3, and Siah2. We also used two PDAC and two HCC cell lines to compare the expressions of HIF-1α, PHD3, and CD44, as well as the production of VEGF in hypoxic condition. The role of PHD3 in regulating HIF-1α expression was further confirmed by siRNA knockdown in a PDAC cell line that highly expressed PHD3. RESULTS: There were significantly fewer microvessels but more cancer stem cells in PDAC specimens compared to HCC specimens. The expression of CD105 was reversely related to the expression of CD44 in PDAC and HCC specimens. PDAC specimens also showed higher expressions of PHD3 but lower expressions of HIF-1α. Similarly, the expression of PHD3 was observed clearly in PDAC cell lines, but was almost completely negative in HCC cell lines. Hypoxic stimulation clearly enhanced HIF-1α expression and VEGF secretion in both HCC cell lines, but did not significantly change in PDAC cell lines. The knockdown of PHD3 in PDAC cells restored the hypoxic-induced HIF-1α expression, which accordingly stimulated the cells’ VEGF secretion. CONCLUSIONS: The enhanced expression of PHD3 might likely contribute to the poor neovascularization and affect the biological characterization in PDAC cancer cells. Springer Japan 2014-12-27 2015 /pmc/articles/PMC4561234/ /pubmed/25542265 http://dx.doi.org/10.1007/s00535-014-1030-3 Text en © The Author(s) 2014 https://creativecommons.org/licenses/by-nc/4.0/ Open AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
spellingShingle Original Article—Liver, Pancreas, and Biliary Tract
Tanaka, Takayuki
Li, Tao-Sheng
Urata, Yoshishige
Goto, Shinji
Ono, Yusuke
Kawakatsu, Miho
Matsushima, Hajime
Hirabaru, Masataka
Adachi, Tomohiko
Kitasato, Amane
Takatsuki, Mitsuhisa
Kuroki, Tamotsu
Eguchi, Susumu
Increased expression of PHD3 represses the HIF-1 signaling pathway and contributes to poor neovascularization in pancreatic ductal adenocarcinoma
title Increased expression of PHD3 represses the HIF-1 signaling pathway and contributes to poor neovascularization in pancreatic ductal adenocarcinoma
title_full Increased expression of PHD3 represses the HIF-1 signaling pathway and contributes to poor neovascularization in pancreatic ductal adenocarcinoma
title_fullStr Increased expression of PHD3 represses the HIF-1 signaling pathway and contributes to poor neovascularization in pancreatic ductal adenocarcinoma
title_full_unstemmed Increased expression of PHD3 represses the HIF-1 signaling pathway and contributes to poor neovascularization in pancreatic ductal adenocarcinoma
title_short Increased expression of PHD3 represses the HIF-1 signaling pathway and contributes to poor neovascularization in pancreatic ductal adenocarcinoma
title_sort increased expression of phd3 represses the hif-1 signaling pathway and contributes to poor neovascularization in pancreatic ductal adenocarcinoma
topic Original Article—Liver, Pancreas, and Biliary Tract
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561234/
https://www.ncbi.nlm.nih.gov/pubmed/25542265
http://dx.doi.org/10.1007/s00535-014-1030-3
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