PMID- 25040744
OWN - NLM
STAT- MEDLINE
DCOM- 20141117
LR  - 20211021
IS  - 1349-7006 (Electronic)
IS  - 1347-9032 (Print)
IS  - 1347-9032 (Linking)
VI  - 105
IP  - 9
DP  - 2014 Sep
TI  - Kruppel-like factor 8 contributes to hypoxia-induced MDR in gastric cancer cells.
PG  - 1109-15
LID - 10.1111/cas.12483 [doi]
AB  - 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 Kruppel-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-1alpha 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.
CI  - (c) 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on 
      behalf of Japanese Cancer Association.
FAU - Zhang, Hui
AU  - Zhang H
AD  - Department of Oncology, Tangdu Hospital, Fourth Military Medical University, 
      Xi'an, China; Department of Tuberculosis Control and Prevention, Xi'an Center for 
      Disease Control and Prevention, Xi'an, China.
FAU - Sun, Li
AU  - Sun L
FAU - Xiao, Xiao
AU  - Xiao X
FAU - Xie, Rougang
AU  - Xie R
FAU - Liu, Changhao
AU  - Liu C
FAU - Wang, Yafang
AU  - Wang Y
FAU - Wei, Yanling
AU  - Wei Y
FAU - Zhang, Hongbo
AU  - Zhang H
FAU - Liu, Lili
AU  - Liu L
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140908
PL  - England
TA  - Cancer Sci
JT  - Cancer science
JID - 101168776
RN  - 0 (ABCB1 protein, human)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (KLF8 protein, human)
RN  - 0 (Kruppel-Like Transcription Factors)
RN  - 0 (Repressor Proteins)
RN  - 80168379AG (Doxorubicin)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/*genetics/metabolism
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Apoptosis
MH  - Apoptosis Regulatory Proteins/genetics/metabolism
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Doxorubicin/pharmacology
MH  - *Drug Resistance, Multiple
MH  - *Drug Resistance, Neoplasm
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism
MH  - Kruppel-Like Transcription Factors
MH  - Repressor Proteins/*physiology
MH  - Stomach Neoplasms
MH  - Transcription, Genetic
MH  - Transcriptional Activation
PMC - PMC4462403
OTO - NOTNLM
OT  - Gastric cancer cells
OT  - Kruppel-like factor 8
OT  - hypoxia
OT  - multidrug resistance
OT  - normoxia
EDAT- 2014/07/22 06:00
MHDA- 2014/11/18 06:00
PMCR- 2014/09/01
CRDT- 2014/07/22 06:00
PHST- 2014/01/09 00:00 [received]
PHST- 2014/07/02 00:00 [revised]
PHST- 2014/07/04 00:00 [accepted]
PHST- 2014/07/22 06:00 [entrez]
PHST- 2014/07/22 06:00 [pubmed]
PHST- 2014/11/18 06:00 [medline]
PHST- 2014/09/01 00:00 [pmc-release]
AID - 10.1111/cas.12483 [doi]
PST - ppublish
SO  - Cancer Sci. 2014 Sep;105(9):1109-15. doi: 10.1111/cas.12483. Epub 2014 Sep 8.