The forkhead box M1 (FOXM1) expression and antitumor effect of FOXM1 inhibition in malignant rhabdoid tumor
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ORIGINAL ARTICLE – CLINICAL ONCOLOGY
The forkhead box M1 (FOXM1) expression and antitumor effect of FOXM1 inhibition in malignant rhabdoid tumor Yuichi Shibui1 · Kenichi Kohashi1 · Akihiko Tamaki1 · Izumi Kinoshita1 · Yuichi Yamada1 · Hidetaka Yamamoto1 · Tomoaki Taguchi2 · Yoshinao Oda1 Received: 25 August 2020 / Accepted: 22 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract 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. Keywords Malignant rhabdoid tumor · FOXM1 · Cell cycle · FANCD2 · NBS1 Abbreviations MRT Malignant rhabdoid tumor MRTK MRT of the kidney EMRT Extra-renal non-cranial MRT AT/RT Atypical teratoid/rhabdoid tumor ATP Adenosine triphosphate Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00432-020-03438-w) contains supplementary material, which is available to authorized users. * Yoshinao Oda [email protected]‑u.ac.jp 1
Department of Anatomic Pathology Graduate School of Medical Sciences, Kyushu University, Maidashi3‑1‑1, Higashi‑ku, Fukuoka 812‑8582, Japan
Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Maidashi3‑1‑1, Higashi‑ku, Fukuoka 812‑8582, Japan
2
CDK Cyclin-dependent kinase RB Retinoblastoma MYC C-avian myelocytomatosis viral oncogene homolog hemoglobin FOXM1 Forkhead box protein M1 DOX Doxorubicin FANCD2 Fanconi anem
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