PMID- 26296946
OWN - NLM
STAT- MEDLINE
DCOM- 20160607
LR  - 20210109
IS  - 1349-7006 (Electronic)
IS  - 1347-9032 (Print)
IS  - 1347-9032 (Linking)
VI  - 106
IP  - 11
DP  - 2015 Nov
TI  - Transforming growth factor-beta signaling enhancement by long-term exposure to 
      hypoxia in a tumor microenvironment composed of Lewis lung carcinoma cells.
PG  - 1524-33
LID - 10.1111/cas.12773 [doi]
AB  - Transforming growth factor-beta (TGF-beta) is a potent growth inhibitor in normal 
      epithelial cells. However, a number of malignant tumors produce excessive amounts 
      of TGF-beta, which affects the tumor-associated microenvironment by furthering the 
      progression of tumorigenicity. Although it is known that the tumor-associated 
      microenvironment often becomes hypoxic, how hypoxia influences TGF-beta signaling in 
      this microenvironment is unknown. We investigated whether TGF-beta signaling is 
      influenced by long-term exposure to hypoxia in Lewis lung carcinoma (LLC) cells. 
      When the cells were exposed to hypoxia for more than 10 days, their morphology 
      was remarkably changed to a spindle shape, and TGF-beta-induced Smad2 
      phosphorylation was enhanced. Concomitantly, TGF-beta-induced transcriptional 
      activity was augmented under hypoxia, although TGF-beta did not influence the 
      activity of a hypoxia-responsive reporter. Consistently, hypoxia influenced the 
      expression of several TGF-beta target genes. Interestingly, the expressions of TGF-beta 
      type I receptor (TbetaRI), also termed activin receptor like kinase-5 (ALK5), and 
      TGF-beta1 were increased under the hypoxic condition. When we monitored the 
      hypoxia-inducible factor-1 (HIF-1) transcriptional activity by use of green 
      fluorescent protein governed by the hypoxia-responsive element in LLC cells 
      transplanted into mice, TGF-beta-induced Smad2 phosphorylation was upregulated in 
      vivo. Our results demonstrate that long-term exposure to hypoxia might alter 
      responsiveness to TGF-beta signaling and affected the malignancy of LLC cells.
CI  - (c) 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on 
      behalf of Japanese Cancer Association.
FAU - Furuta, Chiaki
AU  - Furuta C
AD  - Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life 
      Sciences, Hachioji, Tokyo, Japan.
FAU - Miyamoto, Tatsuki
AU  - Miyamoto T
AD  - Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life 
      Sciences, Hachioji, Tokyo, Japan.
FAU - Takagi, Takahiro
AU  - Takagi T
AD  - Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life 
      Sciences, Hachioji, Tokyo, Japan.
FAU - Noguchi, Yuri
AU  - Noguchi Y
AD  - Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life 
      Sciences, Hachioji, Tokyo, Japan.
FAU - Kaneko, Jyunya
AU  - Kaneko J
AD  - Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life 
      Sciences, Hachioji, Tokyo, Japan.
FAU - Itoh, Susumu
AU  - Itoh S
AD  - Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo, 
      Japan.
FAU - Watanabe, Takuya
AU  - Watanabe T
AD  - Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life 
      Sciences, Hachioji, Tokyo, Japan.
FAU - Itoh, Fumiko
AU  - Itoh F
AD  - Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life 
      Sciences, Hachioji, Tokyo, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151014
PL  - England
TA  - Cancer Sci
JT  - Cancer science
JID - 101168776
RN  - 0 (Transforming Growth Factor beta)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Carcinoma, Lewis Lung/*pathology
MH  - Cell Hypoxia/*physiology
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Fluorescent Antibody Technique
MH  - Immunoprecipitation
MH  - Mice
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/*physiology
MH  - Transforming Growth Factor beta/*metabolism
MH  - Tumor Microenvironment/*physiology
PMC - PMC4714699
OTO - NOTNLM
OT  - Hypoxia
OT  - Lewis lung carcinoma
OT  - Smad
OT  - transforming growth factor-beta
OT  - tumor microenvironment
EDAT- 2015/08/25 06:00
MHDA- 2016/06/09 06:00
PMCR- 2015/11/01
CRDT- 2015/08/23 06:00
PHST- 2015/04/21 00:00 [received]
PHST- 2015/08/02 00:00 [revised]
PHST- 2015/08/08 00:00 [accepted]
PHST- 2015/08/23 06:00 [entrez]
PHST- 2015/08/25 06:00 [pubmed]
PHST- 2016/06/09 06:00 [medline]
PHST- 2015/11/01 00:00 [pmc-release]
AID - CAS12773 [pii]
AID - 10.1111/cas.12773 [doi]
PST - ppublish
SO  - Cancer Sci. 2015 Nov;106(11):1524-33. doi: 10.1111/cas.12773. Epub 2015 Oct 14.