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Krüppel-like factor 8 contributes to hypoxia-induced MDR in gastric cancer cells
We previously reported that hypoxia-induced MDR in gastric cancer (GC) cells is hypoxia-inducible factor-1 (HIF-1)-dependent. However, the exact mechanisms are still unknown. Our previous study revealed that Krüppel-like factor 8 (KLF8), a novel transcription factor, was associated with malignant ph...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BlackWell Publishing Ltd
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462403/ https://www.ncbi.nlm.nih.gov/pubmed/25040744 http://dx.doi.org/10.1111/cas.12483 |
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author | Zhang, Hui Sun, Li Xiao, Xiao Xie, Rougang Liu, Changhao Wang, Yafang Wei, Yanling Zhang, Hongbo Liu, Lili |
author_facet | Zhang, Hui Sun, Li Xiao, Xiao Xie, Rougang Liu, Changhao Wang, Yafang Wei, Yanling Zhang, Hongbo Liu, Lili |
author_sort | Zhang, Hui |
collection | PubMed |
description | We previously reported that hypoxia-induced MDR in gastric cancer (GC) cells is hypoxia-inducible factor-1 (HIF-1)-dependent. However, the exact mechanisms are still unknown. Our previous study revealed that Krüppel-like factor 8 (KLF8), a novel transcription factor, was associated with malignant phenotype in GC cells. KLF8 is overexpressed in clear cell renal carcinoma lacking von Hippel-Lindau protein function, which resulted in HIF-1 stabilization. Given this association, we hypothesized that KLF8 contributed to hypoxia-induced MDR in GC cells. Initial experiments revealed that hypoxia could increase KLF8 and HIF-1α expressions in GC cells, and KLF8 levels in GC drug-resistant cell lines were higher than in parental cell lines. Subsequent experiments showed that in normoxia, exogenous KLF8 could promote the MDR phenotype; however, blocking KLF8 expression could effectively reverse the MDR phenotype induced by hypoxia. Overexpressed KLF8 increased resistance-associated gene MDR1 mRNA levels, Bcl-2 and P-gp protein levels, and decreased Bax and caspase-3 protein levels in GC cells, and knockout KLF8 reversed these effects. Dual luciferase reporter and ChIP assays showed that KLF8 could promote MDR1 transcriptional activity by combining with KLF8 binding sites located in the upstream of MDR1 transcriptional start site. These results suggest that KLF8 is involved in hypoxia-induced MDR through inhibiting apoptosis and increasing the drug release rate by directly regulating MDR1 transcription. This study aims to discuss whether KLF8 involves in hypoxia-induced multi-drug resistance and its mechanism. Our results showed that hypoxia could increase KLF8 expression in gastric cancer cells. Meanwhile, we found that KLF8 contributed to hypoxia-induced multi-drug resistance via regulating MDR1 directly. Through this research, we found a new target gene of KLF8 and further clarified the mechanism of multi-drug resistance happened in gastric cancer. |
format | Online Article Text |
id | pubmed-4462403 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BlackWell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-44624032015-10-05 Krüppel-like factor 8 contributes to hypoxia-induced MDR in gastric cancer cells Zhang, Hui Sun, Li Xiao, Xiao Xie, Rougang Liu, Changhao Wang, Yafang Wei, Yanling Zhang, Hongbo Liu, Lili Cancer Sci Original Articles We previously reported that hypoxia-induced MDR in gastric cancer (GC) cells is hypoxia-inducible factor-1 (HIF-1)-dependent. However, the exact mechanisms are still unknown. Our previous study revealed that Krüppel-like factor 8 (KLF8), a novel transcription factor, was associated with malignant phenotype in GC cells. KLF8 is overexpressed in clear cell renal carcinoma lacking von Hippel-Lindau protein function, which resulted in HIF-1 stabilization. Given this association, we hypothesized that KLF8 contributed to hypoxia-induced MDR in GC cells. Initial experiments revealed that hypoxia could increase KLF8 and HIF-1α expressions in GC cells, and KLF8 levels in GC drug-resistant cell lines were higher than in parental cell lines. Subsequent experiments showed that in normoxia, exogenous KLF8 could promote the MDR phenotype; however, blocking KLF8 expression could effectively reverse the MDR phenotype induced by hypoxia. Overexpressed KLF8 increased resistance-associated gene MDR1 mRNA levels, Bcl-2 and P-gp protein levels, and decreased Bax and caspase-3 protein levels in GC cells, and knockout KLF8 reversed these effects. Dual luciferase reporter and ChIP assays showed that KLF8 could promote MDR1 transcriptional activity by combining with KLF8 binding sites located in the upstream of MDR1 transcriptional start site. These results suggest that KLF8 is involved in hypoxia-induced MDR through inhibiting apoptosis and increasing the drug release rate by directly regulating MDR1 transcription. This study aims to discuss whether KLF8 involves in hypoxia-induced multi-drug resistance and its mechanism. Our results showed that hypoxia could increase KLF8 expression in gastric cancer cells. Meanwhile, we found that KLF8 contributed to hypoxia-induced multi-drug resistance via regulating MDR1 directly. Through this research, we found a new target gene of KLF8 and further clarified the mechanism of multi-drug resistance happened in gastric cancer. BlackWell Publishing Ltd 2014-09 2014-09-08 /pmc/articles/PMC4462403/ /pubmed/25040744 http://dx.doi.org/10.1111/cas.12483 Text en © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association. http://creativecommons.org/licenses/by-nc/3.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Articles Zhang, Hui Sun, Li Xiao, Xiao Xie, Rougang Liu, Changhao Wang, Yafang Wei, Yanling Zhang, Hongbo Liu, Lili Krüppel-like factor 8 contributes to hypoxia-induced MDR in gastric cancer cells |
title | Krüppel-like factor 8 contributes to hypoxia-induced MDR in gastric cancer cells |
title_full | Krüppel-like factor 8 contributes to hypoxia-induced MDR in gastric cancer cells |
title_fullStr | Krüppel-like factor 8 contributes to hypoxia-induced MDR in gastric cancer cells |
title_full_unstemmed | Krüppel-like factor 8 contributes to hypoxia-induced MDR in gastric cancer cells |
title_short | Krüppel-like factor 8 contributes to hypoxia-induced MDR in gastric cancer cells |
title_sort | krüppel-like factor 8 contributes to hypoxia-induced mdr in gastric cancer cells |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462403/ https://www.ncbi.nlm.nih.gov/pubmed/25040744 http://dx.doi.org/10.1111/cas.12483 |
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