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Transforming growth factor-? signaling enhancement by long-term exposure to hypoxia in a tumor microenvironment composed of Lewis lung carcinoma cells.

ABSTRACT: Transforming growth factor-? (TGF-?) is a potent growth inhibitor in normal epithelial cells. However, a number of malignant tumors produce excessive amounts of TGF-?, 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-? signaling in this microenvironment is unknown. We investigated whether TGF-? 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-?-induced Smad2 phosphorylation was enhanced. Concomitantly, TGF-?-induced transcriptional activity was augmented under hypoxia, although TGF-? did not influence the activity of a hypoxia-responsive reporter. Consistently, hypoxia influenced the expression of several TGF-? target genes. Interestingly, the expressions of TGF-? type I receptor (T?RI), also termed activin receptor like kinase-5 (ALK5), and TGF-?1 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-?-induced Smad2 phosphorylation was upregulated in vivo. Our results demonstrate that long-term exposure to hypoxia might alter responsiveness to TGF-? signaling and affected the malignancy of LLC cells.

SUBMITTER: Furuta C

PROVIDER: S-EPMC4714699 | biostudies-other | 2015 Nov

REPOSITORIES: biostudies-other

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Transforming growth factor-β signaling enhancement by long-term exposure to hypoxia in a tumor microenvironment composed of Lewis lung carcinoma cells.

Furuta Chiaki C Miyamoto Tatsuki T Takagi Takahiro T Noguchi Yuri Y Kaneko Jyunya J Itoh Susumu S Watanabe Takuya T Itoh Fumiko F

Cancer science 20151014 11

Transforming growth factor-β (TGF-β) is a potent growth inhibitor in normal epithelial cells. However, a number of malignant tumors produce excessive amounts of TGF-β, 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-β signaling in this microenvironment is unknown. We investigated whether TGF-β signaling is influenced by long-term e ...[more]

PMID: 26296946

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Dataset Information

Transforming growth factor-? signaling enhancement by long-term exposure to hypoxia in a tumor microenvironment composed of Lewis lung carcinoma cells.

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Transforming growth factor-β signaling enhancement by long-term exposure to hypoxia in a tumor microenvironment composed of Lewis lung carcinoma cells.

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