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.
J Cancer Res Clin Oncol. 2021 May;147(5):1499-1518. doi: 10.1007/s00432-020-03438-w. Epub 2020 Nov 21.
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.
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.
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.
This study demonstrates that FOXM1 may serve as a promising therapeutic target for MRT.
恶性横纹肌样瘤（MRT）是一种罕见的、高度侵袭性肉瘤，其起源细胞不确定。尽管存在强化多模式治疗的现有标准，但 MRT 患者的预后仍非常差。需要为 MRT 患者提供新型抗肿瘤药物。叉头框转录因子 1（FOXM1）过表达，与几种人类恶性肿瘤的发病机制相关。在这项研究中，我们确定了 FOXM1 表达的临床病理和预后价值及其在 MRT 进展中的作用。
我们使用免疫组织化学方法检测了 23 例 MRT 标本中 FOXM1 的表达水平及其临床意义，并进行了临床病理和预后分析。我们还使用小干扰 RNA（siRNA）和 FOXM1 抑制剂在 MRT 细胞系中证明了 FOXM1 下调与肿瘤特征之间的相关性。
组织病理学分析显示，原发性肾 MRT 中 FOXM1 蛋白表达水平显著降低（p=0.032）；然而，其他临床病理特征或生存率没有显著差异。FOXM1 siRNA 和 FOXM1 抑制剂（thiostrepton）在体外成功下调了 FOXM1 的 mRNA 和蛋白表达，FOXM1 的下调抑制了 MRT 细胞系的增殖、对化疗药物的耐药性、迁移、侵袭，并导致细胞周期停滞和细胞凋亡。cDNA 微阵列分析表明，FOXM1 调节 FANCD2 和 NBS1，这是 DNA 损伤修复的关键基因。
本研究表明，FOXM1 可能成为 MRT 的有前途的治疗靶点。
