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

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...

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Bibliographic Details
Published in:PloS one 2017-05, Vol.12 (5), p.e0178064-e0178064
Main Authors: 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
Format: Article
Language:English
Subjects:
Apoptosis
Biology and Life Sciences
Cancer therapies
Cell culture
Cell growth
Cell Line, Tumor
Cell Proliferation
Cell survival
Development and progression
Diagnosis
DNA binding proteins
Female
Gene expression
Genetic aspects
Hospitals
Humans
Hypoxia
Hypoxia-inducible factor 1
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Hypoxia-inducible factor 1a
Hypoxia-inducible factors
Inhibition
Localization
Male
Medical prognosis
Medical research
Medicine and Health Sciences
Metastasis
Middle Aged
Nervous system tumors
Neurilemmoma - metabolism
Neurilemmoma - pathology
Neurilemmoma - therapy
Oxygen - metabolism
Pathology
Physiological aspects
Polymerase Chain Reaction
Prognosis
Proteins
RNA, Small Interfering - genetics
Rodents
Sarcoma
Signal transduction
siRNA
Soft tissue sarcoma
Studies
Surgery
Therapeutic applications
Tumors
Vascular endothelial growth factor
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Summary: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. 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. 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. Inhibition of HIF-1α signaling is a potential treatment option for MPNSTs.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0178064