Hypoxia-inducible factor 1 alpha is a poor prognostic factor and potential therapeutic target in malignant peripheral nerve sheath tumor

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

Research output: Contribution to journalArticle

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
Pages (from-to)e0178064
JournalPLoS One
Volume12
Issue number5
DOIs
Publication statusPublished - 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

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Hypoxia-inducible factor 1 alpha is a poor prognostic factor and potential therapeutic target in malignant peripheral nerve sheath tumor. / Fukushima, Suguru; Endo, Makoto; Matsumoto, Yoshihiro; Fukushi, Jun-Ichi; Matsunobu, Tomoya; Kawaguchi, Ken-Ichi; Setsu, Nokitaka; IIda, Keiichiro; Yokoyama, Nobuhiko; Nakagawa, Makoto; Yahiro, Kenichiro; Oda, Yoshinao; Iwamoto, Yukihide; Nakashima, Yasuharu.

In: PLoS One, Vol. 12, No. 5, 2017, p. e0178064.

Research output: Contribution to journalArticle

Fukushima, Suguru ; Endo, Makoto ; Matsumoto, Yoshihiro ; Fukushi, Jun-Ichi ; Matsunobu, Tomoya ; Kawaguchi, Ken-Ichi ; Setsu, Nokitaka ; IIda, Keiichiro ; Yokoyama, Nobuhiko ; Nakagawa, Makoto ; Yahiro, Kenichiro ; Oda, Yoshinao ; Iwamoto, Yukihide ; Nakashima, Yasuharu. / Hypoxia-inducible factor 1 alpha is a poor prognostic factor and potential therapeutic target in malignant peripheral nerve sheath tumor. In: PLoS One. 2017 ; Vol. 12, No. 5. pp. e0178064.
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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 Ken-Ichi 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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T1 - Hypoxia-inducible factor 1 alpha is a poor prognostic factor and potential therapeutic target in malignant peripheral nerve sheath tumor

AU - Fukushima, Suguru

AU - Endo, Makoto

AU - Matsumoto, Yoshihiro

AU - Fukushi, Jun-Ichi

AU - Matsunobu, Tomoya

AU - Kawaguchi, Ken-Ichi

AU - Setsu, Nokitaka

AU - IIda, Keiichiro

AU - Yokoyama, Nobuhiko

AU - Nakagawa, Makoto

AU - Yahiro, Kenichiro

AU - Oda, Yoshinao

AU - Iwamoto, Yukihide

AU - Nakashima, Yasuharu

PY - 2017

Y1 - 2017

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.

U2 - 10.1371/journal.pone.0178064

DO - 10.1371/journal.pone.0178064

M3 - Article

VL - 12

SP - e0178064

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 5

ER -