Potential therapeutic target in malignant peripheral nerve sheath tumor

Suguru Fukushima, Makoto Endo, Yoshihiro Matsumoto, Jun-Ichi Fukushi, Tomoya Matsunobu, Kenichi Kawaguchi, Nokitaka Setsu, Keiichiro Iida, Nobuhiko Yokoyama, Makoto Nakagawa, Kenichiro Yahiro, Yoshinao Oda, Yukihide Iwamoto, Yasuharu Nakashima

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. Hypoxia-inducible factor 1 (HIF-1) plays a crucial role in the cellular response to hypoxia and regulates the expression of multiple genes involved in tumor progression in various cancers. However, the importance of the expression of HIF-1α in MPNSTs is unclear. Methods The expression of HIF-1α was examined immunohistochemically in 82 MPNST specimens. Cell culture assays of human MPNST cells under normoxic and hypoxic conditions were used to evaluate the impact of anti-HIF-1α.specific siRNA inhibition on cell survival. A screening kit was employed to identify small molecules that inhibited HIF-1α. Results The nuclear expression of HIF-1α was positive in 75.6% of MPNST samples (62/82 cases). Positivity for HIF-1α was a significant poor prognostic factor both in univariate (P = 0.048) and multivariate (P ≤ 0.0001) analyses. HIF-1α knockdown abrogated MPNST cell growth, inducing apoptosis. Finally, chetomin, an inhibitor of HIF-1α, effectively inhibited the growth of MPNST cells and induced their apoptosis. Conclusion Inhibition of HIF-1α signaling is a potential treatment option for MPNSTs.

Original languageEnglish
Article numbere0178064
JournalPloS one
Volume12
Issue number5
DOIs
Publication statusPublished - May 1 2017

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Hypoxia-Inducible Factor 1
peripheral nerves
Neurilemmoma
Tumors
therapeutics
neoplasms
Therapeutics
apoptosis
hypoxia-inducible factor 1
Apoptosis
normoxia
sarcoma
Cell growth
Growth
small interfering RNA
Cell culture
anaerobic conditions
Sarcoma
Small Interfering RNA
prognosis

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Potential therapeutic target in malignant peripheral nerve sheath tumor. / Fukushima, Suguru; Endo, Makoto; Matsumoto, Yoshihiro; Fukushi, Jun-Ichi; Matsunobu, Tomoya; Kawaguchi, Kenichi; Setsu, Nokitaka; Iida, Keiichiro; Yokoyama, Nobuhiko; Nakagawa, Makoto; Yahiro, Kenichiro; Oda, Yoshinao; Iwamoto, Yukihide; Nakashima, Yasuharu.

In: PloS one, Vol. 12, No. 5, e0178064, 01.05.2017.

Research output: Contribution to journalArticle

Fukushima, Suguru ; Endo, Makoto ; Matsumoto, Yoshihiro ; Fukushi, Jun-Ichi ; Matsunobu, Tomoya ; Kawaguchi, Kenichi ; Setsu, Nokitaka ; Iida, Keiichiro ; Yokoyama, Nobuhiko ; Nakagawa, Makoto ; Yahiro, Kenichiro ; Oda, Yoshinao ; Iwamoto, Yukihide ; Nakashima, Yasuharu. / Potential therapeutic target in malignant peripheral nerve sheath tumor. In: PloS one. 2017 ; Vol. 12, No. 5.
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abstract = "Background Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. Hypoxia-inducible factor 1 (HIF-1) plays a crucial role in the cellular response to hypoxia and regulates the expression of multiple genes involved in tumor progression in various cancers. However, the importance of the expression of HIF-1α in MPNSTs is unclear. Methods The expression of HIF-1α was examined immunohistochemically in 82 MPNST specimens. Cell culture assays of human MPNST cells under normoxic and hypoxic conditions were used to evaluate the impact of anti-HIF-1α.specific siRNA inhibition on cell survival. A screening kit was employed to identify small molecules that inhibited HIF-1α. Results The nuclear expression of HIF-1α was positive in 75.6{\%} of MPNST samples (62/82 cases). Positivity for HIF-1α was a significant poor prognostic factor both in univariate (P = 0.048) and multivariate (P ≤ 0.0001) analyses. HIF-1α knockdown abrogated MPNST cell growth, inducing apoptosis. Finally, chetomin, an inhibitor of HIF-1α, effectively inhibited the growth of MPNST cells and induced their apoptosis. Conclusion Inhibition of HIF-1α signaling is a potential treatment option for MPNSTs.",
author = "Suguru Fukushima and Makoto Endo and Yoshihiro Matsumoto and Jun-Ichi Fukushi and Tomoya Matsunobu and Kenichi Kawaguchi and Nokitaka Setsu and Keiichiro Iida and Nobuhiko Yokoyama and Makoto Nakagawa and Kenichiro Yahiro and Yoshinao Oda and Yukihide Iwamoto and Yasuharu Nakashima",
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AU - Matsumoto, Yoshihiro

AU - Fukushi, Jun-Ichi

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AU - Kawaguchi, Kenichi

AU - Setsu, Nokitaka

AU - Iida, Keiichiro

AU - Yokoyama, Nobuhiko

AU - Nakagawa, Makoto

AU - Yahiro, Kenichiro

AU - Oda, Yoshinao

AU - Iwamoto, Yukihide

AU - Nakashima, Yasuharu

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N2 - Background Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. Hypoxia-inducible factor 1 (HIF-1) plays a crucial role in the cellular response to hypoxia and regulates the expression of multiple genes involved in tumor progression in various cancers. However, the importance of the expression of HIF-1α in MPNSTs is unclear. Methods The expression of HIF-1α was examined immunohistochemically in 82 MPNST specimens. Cell culture assays of human MPNST cells under normoxic and hypoxic conditions were used to evaluate the impact of anti-HIF-1α.specific siRNA inhibition on cell survival. A screening kit was employed to identify small molecules that inhibited HIF-1α. Results The nuclear expression of HIF-1α was positive in 75.6% of MPNST samples (62/82 cases). Positivity for HIF-1α was a significant poor prognostic factor both in univariate (P = 0.048) and multivariate (P ≤ 0.0001) analyses. HIF-1α knockdown abrogated MPNST cell growth, inducing apoptosis. Finally, chetomin, an inhibitor of HIF-1α, effectively inhibited the growth of MPNST cells and induced their apoptosis. Conclusion Inhibition of HIF-1α signaling is a potential treatment option for MPNSTs.

AB - Background Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. Hypoxia-inducible factor 1 (HIF-1) plays a crucial role in the cellular response to hypoxia and regulates the expression of multiple genes involved in tumor progression in various cancers. However, the importance of the expression of HIF-1α in MPNSTs is unclear. Methods The expression of HIF-1α was examined immunohistochemically in 82 MPNST specimens. Cell culture assays of human MPNST cells under normoxic and hypoxic conditions were used to evaluate the impact of anti-HIF-1α.specific siRNA inhibition on cell survival. A screening kit was employed to identify small molecules that inhibited HIF-1α. Results The nuclear expression of HIF-1α was positive in 75.6% of MPNST samples (62/82 cases). Positivity for HIF-1α was a significant poor prognostic factor both in univariate (P = 0.048) and multivariate (P ≤ 0.0001) analyses. HIF-1α knockdown abrogated MPNST cell growth, inducing apoptosis. Finally, chetomin, an inhibitor of HIF-1α, effectively inhibited the growth of MPNST cells and induced their apoptosis. Conclusion Inhibition of HIF-1α signaling is a potential treatment option for MPNSTs.

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