title: Expression of Forkhead box M1 in soft tissue leiomyosarcoma: Clinicopathologic and in vitro study using a newly established cell line.
abstract: Leiomyosarcoma (LMS) of soft tissue is a sarcoma with smooth-muscle differentiation, and conventional chemotherapy does not improve its outcome. The application of novel antitumor agents and precise prognostication has been demanded. The expression of the protein Forkhead box M1 (FOXM1), a member of the FOX family, is considered an independent predictor of poor survival in many cancers and sarcomas. However, the expression status of FOXM1 in LMS is poorly understood. The purposes of this study were to examine the correlation between the expression of FOXM1 and clinicopathologic or prognostic factors and to clarify the efficacy of FOXM1 target therapy in LMS. We evaluated the immunohistochemical expressions of FOXM1 using 123 LMS tumor specimens. Univariate and multivariate survival analyses revealed that FOXM1 expression was associated with poor prognosis in LMS. An in vitro study was then carried out to examine the antitumor effect of a FOXM1 inhibitor (thiostrepton) and siRNA on a novel LMS cell line, TC616. We also assessed the efficacy of the combined use of doxorubicin and thiostrepton. Thiostrepton showed dose-dependent antitumor activity and TC616 cells treated with the combination of thiostrepton and doxorubicin showed lower proliferation compared to those treated with either drug individually. FOXM1 interruption by siRNA decreased cell proliferation and increased chemosensitivity. In conclusion, FOXM1 has potential to be a therapeutic target for LMS.
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Maekawa
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kohashi
authors.affiliation: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Nokitaka
authors.initials: N
authors.lastname: Setsu
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kuda
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Iura
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takeaki
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Matsunobu
authors.affiliation: Division of Cancer Immunotherapy, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakatsura
authors.affiliation: Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D053208:Kaplan-Meier Estimate; D007890:Leiomyosarcoma / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D034741:RNA, Small Interfering; D012983:Soft Tissue Neoplasms / Q000401:mortality / Q000473:pathology*; D013883:Thiostrepton / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D004317:Doxorubicin; D013883:Thiostrepton
keywords: FOXM1; immunohistochemistry; leiomyosarcoma; prognosis; thiostrepton