Krüppel‐like factor 8 contributes to hypoxia‐induced MDR in gastric cancer cells

Cancer Science

Hui Zhang³  Li Sun¹  Xiao Xiao¹  Rougang Xie²  Changhao Liu¹  Yafang Wang¹  Yanling Wei¹  Hongbo Zhang¹ 

[1]State Key Laboratory of Cancer Biology, Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China

[2]Institute of Neuroscience, Fourth Military Medical University, Xi'an, China

[3]Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China

关键词: Gastric cancer cells;    hypoxia;    Krüppel‐like factor 8;    multidrug resistance;    normoxia;   

DOI  :  10.1111/cas.12483

来源: Wiley

【 摘 要 】

Abstract

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.

【 授权许可】

CC BY-NC   
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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