The forkhead box M1 (FOXM1) expression and antitumor effect of FOXM1 inhibition in malignant rhabdoid tumor

• Published in: Journal of cancer research and clinical oncology 2021-05, Vol.147 (5), p.1499-1518
• Main Authors: Shibui, Yuichi, Kohashi, Kenichi, Tamaki, Akihiko, Kinoshita, Izumi, Yamada, Yuichi, Yamamoto, Hidetaka, Taguchi, Tomoaki, Oda, Yoshinao
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Antitumor activity; Antitumor agents; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Cancer Research; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Cycle Checkpoints - genetics; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - genetics; Cell proliferation; Cell Proliferation - drug effects; Cell Proliferation - genetics; Chemotherapy; DNA damage; DNA Damage - drug effects; DNA Damage - genetics; DNA microarrays; DNA repair; Down-Regulation - drug effects; Down-Regulation - genetics; Drug resistance; Fanconi Anemia Complementation Group D2 Protein - genetics; Female; Forkhead Box Protein M1 - antagonists & inhibitors; Forkhead Box Protein M1 - genetics; Forkhead protein; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Hematology; Humans; Immunohistochemistry; Immunohistochemistry - methods; Infant; Internal Medicine; Male; Malignant rhabdoid tumor; Medical prognosis; Medicine; Medicine & Public Health; Nuclear Proteins - genetics; Oncology; Original Article – Clinical Oncology; Prognosis; Protein expression; Rhabdoid Tumor - drug therapy; Rhabdoid Tumor - genetics; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Sarcoma; siRNA; Survival Rate; Therapeutic targets; Thiostrepton; Thiostrepton - pharmacology
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-020-03438-w

Purpose Malignant rhabdoid tumor (MRT) is a rare, highly aggressive sarcoma with an uncertain cell of origin. Despite the existing standard of intensive multimodal therapy, the prognosis of patients with MRT is very poor. Novel antitumor agents are needed for MRT patients. Forkhead box transcription factor 1 (FOXM1) is overexpressed and is correlated with the pathogenesis in several human malignancies. In this study, we identified the clinicopathological and prognostic values of the expression of FOXM1 and its roles in the progression of MRT. Methods We investigated the FOXM1 expression levels and their clinical significance in 23 MRT specimens using immunohistochemistry and performed clinicopathologic and prognostic analyses. We also demonstrated correlations between the downregulation of FOXM1 and oncological characteristics using small interfering RNA (siRNA) and FOXM1 inhibitor in MRT cell lines. Results Histopathological analyses revealed that primary renal MRTs showed significantly low FOXM1 protein expression levels ( p  = 0.032); however, there were no significant differences in other clinicopathological characteristics or the survival rate. FOXM1 siRNA and FOXM1 inhibitor (thiostrepton) successfully downregulated the mRNA and protein expression of FOXM1 in vitro and the downregulation of FOXM1 inhibited cell proliferation, drug resistance to chemotherapeutic agents, migration, invasion, and caused the cell cycle arrest and apoptosis of MRT cell lines. A cDNA microarray analysis showed that FOXM1 regulated FANCD2 and NBS1, which are key genes for DNA damage repair. Conclusion This study demonstrates that FOXM1 may serve as a promising therapeutic target for MRT.