Cargando…

Blocking heme oxygenase-1 by zinc protoporphyrin reduces tumor hypoxia-mediated VEGF release and inhibits tumor angiogenesis as a potential therapeutic agent against colorectal cancer

BACKGROUND: Hypoxia in tumor niche is one of important factors to start regeneration of blood vessels, leading to increase survival, proliferation, and invasion in cancer cells. Under hypoxia microenvironment, furthermore, steadily increased hypoxia-inducible factor-1α (HIF-1α) is observed, and can...

Descripción completa

Detalles Bibliográficos
Autores principales: Cheng, Chun-Chia, Guan, Siao-Syun, Yang, Hao-Jhih, Chang, Chun-Chao, Luo, Tsai-Yueh, Chang, Jungshan, Ho, Ai-Sheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4730655/
https://www.ncbi.nlm.nih.gov/pubmed/26822586
http://dx.doi.org/10.1186/s12929-016-0219-6
_version_ 1782412439616225280
author Cheng, Chun-Chia
Guan, Siao-Syun
Yang, Hao-Jhih
Chang, Chun-Chao
Luo, Tsai-Yueh
Chang, Jungshan
Ho, Ai-Sheng
author_facet Cheng, Chun-Chia
Guan, Siao-Syun
Yang, Hao-Jhih
Chang, Chun-Chao
Luo, Tsai-Yueh
Chang, Jungshan
Ho, Ai-Sheng
author_sort Cheng, Chun-Chia
collection PubMed
description BACKGROUND: Hypoxia in tumor niche is one of important factors to start regeneration of blood vessels, leading to increase survival, proliferation, and invasion in cancer cells. Under hypoxia microenvironment, furthermore, steadily increased hypoxia-inducible factor-1α (HIF-1α) is observed, and can increase vascular endothelial growth factor (VEGF) expression and promote angiogenesis. Zinc protoporphyrin (ZnPP), a heme oxygenase-1 (HO-1) inhibitor, is potential to inhibit tumor proliferation and progression. However, the mechanism of ZnPP in inhibition of tumor is not completely clear. We hypothesize that ZnPP may modulate HIF-1α through inhibiting HO-1, and then inhibit angiogenesis and tumor progression. This study aimed to dissect the mechanism of ZnPP in tumor suppression. RESULTS: We observed the amount of VEGF was increased in the sera of the colorectal cancer (CRC) patients (n = 34, p < 0.05). Furthermore, increased VEGF expression was also measured in colorectal cancer cells, HCT-15, culturing under mimicking hypoxic condition. It suggested that hypoxia induced VEGF production from cancer cells. VEGF production was significantly reduced from HCT-15 cells after exposure to HIF-1α inhibitor KC7F2, suggesting that HIF-1α regulated VEGF production. Moreover, we observed that the HO-1inhibitor ZnPP inhibited the expressions of HIF-1α and VEGF coupled with cell proliferations of HCT-15 cells, suggesting that ZnPP blocked HIF-1α expression, and then inhibited the consequent VEGF production. In the xenograft model, we also observed that the animals exposed to ZnPP displayed much smaller tumor nodules and less degree of angiogenesis with decreased expression of the angiogenesis marker, αvβ3 integrin, compared to that in normal control. CONCLUSIONS: This study demonstrated that VEGF level in serum was elevated in the patients with CRC. The HO-1 inhibitor, ZnPP, possessed the properties of anti-tumor agent by decreasing HIF-1α levels, blocking VEGF production, impairing tumor angiogenesis, and inhibiting tumor growth.
format Online
Article
Text
id pubmed-4730655
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-47306552016-01-29 Blocking heme oxygenase-1 by zinc protoporphyrin reduces tumor hypoxia-mediated VEGF release and inhibits tumor angiogenesis as a potential therapeutic agent against colorectal cancer Cheng, Chun-Chia Guan, Siao-Syun Yang, Hao-Jhih Chang, Chun-Chao Luo, Tsai-Yueh Chang, Jungshan Ho, Ai-Sheng J Biomed Sci Research BACKGROUND: Hypoxia in tumor niche is one of important factors to start regeneration of blood vessels, leading to increase survival, proliferation, and invasion in cancer cells. Under hypoxia microenvironment, furthermore, steadily increased hypoxia-inducible factor-1α (HIF-1α) is observed, and can increase vascular endothelial growth factor (VEGF) expression and promote angiogenesis. Zinc protoporphyrin (ZnPP), a heme oxygenase-1 (HO-1) inhibitor, is potential to inhibit tumor proliferation and progression. However, the mechanism of ZnPP in inhibition of tumor is not completely clear. We hypothesize that ZnPP may modulate HIF-1α through inhibiting HO-1, and then inhibit angiogenesis and tumor progression. This study aimed to dissect the mechanism of ZnPP in tumor suppression. RESULTS: We observed the amount of VEGF was increased in the sera of the colorectal cancer (CRC) patients (n = 34, p < 0.05). Furthermore, increased VEGF expression was also measured in colorectal cancer cells, HCT-15, culturing under mimicking hypoxic condition. It suggested that hypoxia induced VEGF production from cancer cells. VEGF production was significantly reduced from HCT-15 cells after exposure to HIF-1α inhibitor KC7F2, suggesting that HIF-1α regulated VEGF production. Moreover, we observed that the HO-1inhibitor ZnPP inhibited the expressions of HIF-1α and VEGF coupled with cell proliferations of HCT-15 cells, suggesting that ZnPP blocked HIF-1α expression, and then inhibited the consequent VEGF production. In the xenograft model, we also observed that the animals exposed to ZnPP displayed much smaller tumor nodules and less degree of angiogenesis with decreased expression of the angiogenesis marker, αvβ3 integrin, compared to that in normal control. CONCLUSIONS: This study demonstrated that VEGF level in serum was elevated in the patients with CRC. The HO-1 inhibitor, ZnPP, possessed the properties of anti-tumor agent by decreasing HIF-1α levels, blocking VEGF production, impairing tumor angiogenesis, and inhibiting tumor growth. BioMed Central 2016-01-28 /pmc/articles/PMC4730655/ /pubmed/26822586 http://dx.doi.org/10.1186/s12929-016-0219-6 Text en © Cheng et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Cheng, Chun-Chia
Guan, Siao-Syun
Yang, Hao-Jhih
Chang, Chun-Chao
Luo, Tsai-Yueh
Chang, Jungshan
Ho, Ai-Sheng
Blocking heme oxygenase-1 by zinc protoporphyrin reduces tumor hypoxia-mediated VEGF release and inhibits tumor angiogenesis as a potential therapeutic agent against colorectal cancer
title Blocking heme oxygenase-1 by zinc protoporphyrin reduces tumor hypoxia-mediated VEGF release and inhibits tumor angiogenesis as a potential therapeutic agent against colorectal cancer
title_full Blocking heme oxygenase-1 by zinc protoporphyrin reduces tumor hypoxia-mediated VEGF release and inhibits tumor angiogenesis as a potential therapeutic agent against colorectal cancer
title_fullStr Blocking heme oxygenase-1 by zinc protoporphyrin reduces tumor hypoxia-mediated VEGF release and inhibits tumor angiogenesis as a potential therapeutic agent against colorectal cancer
title_full_unstemmed Blocking heme oxygenase-1 by zinc protoporphyrin reduces tumor hypoxia-mediated VEGF release and inhibits tumor angiogenesis as a potential therapeutic agent against colorectal cancer
title_short Blocking heme oxygenase-1 by zinc protoporphyrin reduces tumor hypoxia-mediated VEGF release and inhibits tumor angiogenesis as a potential therapeutic agent against colorectal cancer
title_sort blocking heme oxygenase-1 by zinc protoporphyrin reduces tumor hypoxia-mediated vegf release and inhibits tumor angiogenesis as a potential therapeutic agent against colorectal cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4730655/
https://www.ncbi.nlm.nih.gov/pubmed/26822586
http://dx.doi.org/10.1186/s12929-016-0219-6
work_keys_str_mv AT chengchunchia blockinghemeoxygenase1byzincprotoporphyrinreducestumorhypoxiamediatedvegfreleaseandinhibitstumorangiogenesisasapotentialtherapeuticagentagainstcolorectalcancer
AT guansiaosyun blockinghemeoxygenase1byzincprotoporphyrinreducestumorhypoxiamediatedvegfreleaseandinhibitstumorangiogenesisasapotentialtherapeuticagentagainstcolorectalcancer
AT yanghaojhih blockinghemeoxygenase1byzincprotoporphyrinreducestumorhypoxiamediatedvegfreleaseandinhibitstumorangiogenesisasapotentialtherapeuticagentagainstcolorectalcancer
AT changchunchao blockinghemeoxygenase1byzincprotoporphyrinreducestumorhypoxiamediatedvegfreleaseandinhibitstumorangiogenesisasapotentialtherapeuticagentagainstcolorectalcancer
AT luotsaiyueh blockinghemeoxygenase1byzincprotoporphyrinreducestumorhypoxiamediatedvegfreleaseandinhibitstumorangiogenesisasapotentialtherapeuticagentagainstcolorectalcancer
AT changjungshan blockinghemeoxygenase1byzincprotoporphyrinreducestumorhypoxiamediatedvegfreleaseandinhibitstumorangiogenesisasapotentialtherapeuticagentagainstcolorectalcancer
AT hoaisheng blockinghemeoxygenase1byzincprotoporphyrinreducestumorhypoxiamediatedvegfreleaseandinhibitstumorangiogenesisasapotentialtherapeuticagentagainstcolorectalcancer