J Cancer 2016; 7(7):823-830. doi:10.7150/jca.14461

Research Paper

Prognostic Significance of Forkhead Box M1 (FOXM1) Expression and Antitumor Effect of FOXM1 Inhibition in Angiosarcoma

Takamichi Ito1,2, Kenichi Kohashi1, Yuichi Yamada1, Takeshi Iwasaki1, Akira Maekawa1, Masaaki Kuda1, Daichi Hoshina3, Riichiro Abe3, Masutaka Furue2, Yoshinao Oda1✉

1. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
2. Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
3. Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Abstract

Background: The prognosis of angiosarcoma is poor and a novel treatment option for the disease is desired. The aim of this study was to investigate the prognostic significance of Forkhead box M1 (FOXM1), a transcription factor that regulates cell-cycle progression and various crucial processes in tumor progression, and its potential as a new therapeutic target.

Methods: We investigated 125 angiosarcoma clinical samples (94 primary lesions and 31 metastatic lesions in 94 patients) and a human angiosarcoma cell line (HAMON) using immunohistochemical staining and molecular biological approaches. FOXM1 expression in angiosarcoma samples was also compared with that in Kaposi's sarcomas (n = 13), epithelioid hemangioendotheliomas (n = 13) and benign hemangiomas (n = 10).

Results: Patients with FOXM1-overexpressing angiosarcoma had significantly shorter survival (both for disease-specific survival [DSS] and event-free survival [EFS]) than other patients (5-year DSS, 23.5% vs. 47.1%, P = 0.013; and 5-year EFS, 5.5% vs. 28.7%, P = 0.004). FOXM1 overexpression was also an independent prognostic factor for both DSS and EFS in Cox multivariate analyses (hazard ratio [HR] 2.84, 95% confidence interval [CI] 1.10-5.81, P = 0.039; and HR 4.16, 95%CI 2.03-8.67, P = 0.0001, respectively). FOXM1 inhibition using both small interfering RNA and a specific inhibitor (thiostrepton) suppressed cell proliferation of the angiosarcoma cell line. Furthermore, FOXM1 inhibition improved the chemosensitivity to docetaxel in vitro.

Conclusions: FOXM1 inhibition may be a potential therapeutic option for angiosarcoma.

Keywords: Forkhead box M1, angiosarcoma, Kaposi's sarcoma, prognosis, treatment, siRNA, docetaxel, thiostrepton.

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How to cite this article:
Ito T, Kohashi K, Yamada Y, Iwasaki T, Maekawa A, Kuda M, Hoshina D, Abe R, Furue M, Oda Y. Prognostic Significance of Forkhead Box M1 (FOXM1) Expression and Antitumor Effect of FOXM1 Inhibition in Angiosarcoma. J Cancer 2016; 7(7):823-830. doi:10.7150/jca.14461. Available from http://www.jcancer.org/v07p0823.htm