Abstract
BackgroundMalignant 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.MethodsThe 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.ResultsThe 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.ConclusionInhibition of HIF-1α signaling is a potential treatment option for MPNSTs.
Highlights
Malignant peripheral nerve sheath tumor (MPNST) is one of several highly malignant soft tissue sarcomas (STSs), with an annual incidence of about 5 per million [1]
Multivariate analysis demonstrated that Hypoxia-inducible factor (HIF)-1α positivity was an independent prognostic factor (P < 0.0001), as was MIB-1 positivity (P < 0.0001), percentage necrotic area >50% (P = 0.039), and AJCC stage (P = 0.0036) (Table 3)
HIF-1α positive specimens showed significantly more cases with >50% necrosis, but there was no significant association between HIF-1α and the status of the other parameters (Table 1)
Summary
Malignant peripheral nerve sheath tumor (MPNST) is one of several highly malignant soft tissue sarcomas (STSs), with an annual incidence of about 5 per million [1]. Half of MPNSTs are associated with neurofibromatosis type 1 (NF 1), while the other half are sporadic. As in cases of other histological types of STS, the combination of doxorubicin and ifosfamide is recommended for MPNSTs; the response rate is unsatisfactory (21%) [6]. No new drugs effective against MPNSTs have been developed far [7]. Identifying new therapeutic targets and effective novel agents against MPNSTs is essential to improve the survival of patients with this condition. Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. The importance of the expression of HIF-1α in MPNSTs is unclear
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