TY - JOUR
T1 - 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
N1 - Funding Information:
The SCADS Inhibitor Kit was kindly provided by the Screening Committee of Anticancer Drugs, supported by a Grant-in-Aid for Scientific Research on Innovative Areas, Scientific Support Programs for Cancer Research, from The Ministry of Education, Culture, Sports, Science and Technology of Japan. We are greatly appreciative of Dr. Junji Kishimoto for his helpful contribution in statistics. This work was supported by Grants-in-Aid for Scientific Research (23592192, 25293325, and 26713046) from the Japan Society for the Promotion of Science, and a Grant-in-Aid for Clinical Research Evidence–Based Medicine and Cancer Research from the Ministry of Health, Labour and Welfare of Japan (Y. Iwamoto).
Funding Information:
Human MPNST cell line FMS-1 was kindly provided by M. Hakozaki (First Department of Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan) []; HS-Sch-2 was provided by the RIKEN BRC through the National Bio-Resource Project of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan; FU-SFT8611 and FU-SFT9817 were established by M. Aoki and H. Iwasaki (Department of Pathology, Fukuoka University School of Medicine, Fukuoka, Japan) []. FMS-1 cells were cultured in RPMI-1640; HS-Sch-2 was maintained in Dulbecco’s modified Eagle’s medium (DMEM); FU-SFT8611 and FU-SFT9817 were cultured in DMEM/F-12. Each medium was supplemented with 10% fetal bovine serum (FBS) (HyClone Laboratories, Inc., Logan, UT, USA), 100 units per ml penicillin, and 100 μg per ml streptomycin at 37°C in an atmosphere of 5% CO. To produce a hypoxic culture condition, the BIONIX-3 hypoxic culture kit was used (Sugiyama-Gen, Tokyo, Japan). Short tandem repeat analysis was performed in MPNST cell lines (Takara Bio, Otsu, Japan). In HS-Sch-2, the evaluation value was 0.944, and the identity of the cell line in the database was confirmed. FMS-1, FU-SFT8611, and FU-SFT9817 were not registered in the database. 2
Publisher Copyright:
© 2017 Fukushima et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2017/5
Y1 - 2017/5
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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U2 - 10.1371/journal.pone.0178064
DO - 10.1371/journal.pone.0178064
M3 - Article
C2 - 28558056
AN - SCOPUS:85020041326
SN - 1932-6203
VL - 12
JO - PLoS One
JF - PLoS One
IS - 5
M1 - e0178064
ER -
