Repressive role of stabilized hypoxia inducible factor 1α expression on transforming growth factor β-induced extracellular matrix production in lung cancer cells.

Authors:
Akira Ando
Akira Ando
Kansai Medical University
Japan
Naozumi Hashimoto
Naozumi Hashimoto
Nagoya University Graduate School of Medicine
Koji Sakamoto
Koji Sakamoto
Juntendo University
Japan
Norihito Omote
Norihito Omote
Nagoya University Graduate School of Medicine
Shinichi Miyazaki
Shinichi Miyazaki
Mie University Graduate School of Medicine
津市 | Japan
Yoshio Nakahara
Yoshio Nakahara
Graduate School of Engineering
Kazuyoshi Imaizumi
Kazuyoshi Imaizumi
Fujita Health University
Tsutomu Kawabe
Tsutomu Kawabe
Nagoya University Graduate School of Medicine
Nagoya | Japan

Cancer Sci 2019 Jun 13;110(6):1959-1973. Epub 2019 May 13.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Activation of transforming growth factor β (TGF-β) combined with persistent hypoxia often affects the tumor microenvironment. Disruption of cadherin/catenin complexes induced by these stimulations yields aberrant extracellular matrix (ECM) production, characteristics of epithelial-mesenchymal transition (EMT). Hypoxia-inducible factors (HIF), the hallmark of the response to hypoxia, play differential roles during development of diseases. Recent studies show that localization of cadherin/catenin complexes at the cell membrane might be tightly regulated by protein phosphatase activity. We aimed to investigate the role of stabilized HIF-1α expression by protein phosphatase activity on dissociation of the E-cadherin/β-catenin complex and aberrant ECM expression in lung cancer cells under stimulation by TGF-β. By using lung cancer cells treated with HIF-1α stabilizers or carrying doxycycline-dependent HIF-1α deletion or point mutants, we investigated the role of stabilized HIF-1α expression on TGF-β-induced EMT in lung cancer cells. Furthermore, the underlying mechanisms were determined by inhibition of protein phosphatase activity. Persistent stimulation by TGF-β and hypoxia induced EMT phenotypes in H358 cells in which stabilized HIF-1α expression was inhibited. Stabilized HIF-1α protein expression inhibited the TGF-β-stimulated appearance of EMT phenotypes across cell types and species, independent of de novo vascular endothelial growth factor A (VEGFA) expression. Inhibition of protein phosphatase 2A activity abrogated the HIF-1α-induced repression of the TGF-β-stimulated appearance of EMT phenotypes. This is the first study to show a direct role of stabilized HIF-1α expression on inhibition of TGF-β-induced EMT phenotypes in lung cancer cells, in part, through protein phosphatase activity.

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Source
http://dx.doi.org/10.1111/cas.14027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549927PMC
June 2019

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References

(Supplied by CrossRef)
Regulation of cadherin‐mediated adhesion in morphogenesis
Gumbiner BM et al.
Nat Rev Mol Cell Biol 2005

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