Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Pediatric Surgery, Faculty of Medicine, University of Tsukuba Hospital, Ibaraki, Japan.
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Pathology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.
Lab Invest. 2024 Aug;104(8):102093. doi: 10.1016/j.labinv.2024.102093. Epub 2024 Jun 9.
Epithelioid sarcoma (ES) is a rare aggressive sarcoma that, unlike most soft-tissue sarcomas, shows a tendency toward local recurrence and lymph node metastasis. Novel antitumor agents are needed for ES patients. Forkhead box transcription factor 1 (FOXM1) is a member of the Forkhead transcription factor family and is associated with multiple oncogenic functions; FOXM1 is known to be overexpressed and correlated with pathogenesis in various malignancies. In this study, we immunohistochemically analyzed FOXM1 expression levels and their clinical, clinicopathologic, and prognostic significance in 38 ES specimens. In addition, to investigate potential correlations between FOXM1 downregulation and oncologic characteristics, we treated ES cell lines with thiostrepton, a naturally occurring antibiotic that inhibits both small interfering RNA (siRNA) and FOXM1. In the analyses using ES samples, all 38 specimens were diagnosed as positive for FOXM1 by immunohistochemistry. We separated specimens into high (n = 19) and low (n = 19) FOXM1-protein expression groups by staining index score, and into large (n = 12), small (n = 25), and unknown (n = 1) tumor-size groups using a cutoff of 5 cm maximum diameter. Although there were significantly more samples with high FOXM1 expression in the large tumor group (P = .013), there were no significant differences with respect to age (P = 1.00), sex (P = .51), primary site of origin (P = .74), histologic subtypes (P = 1.00), depth (P = .74), or survival rate (P = .288) between the high and low FOXM1-protein expression groups. In the in vitro experiments using ES cell lines, FOXM1 siRNA and thiostrepton successfully downregulated FOXM1 mRNA and protein expression. Furthermore, downregulation of FOXM1 inhibited cell proliferation, drug resistance against chemotherapeutic agents, migration, and invasion and caused cell cycle arrest in the ES cell lines. Finally, cDNA microarray analysis data showed that FOXM1 regulated cIAP2, which is one of the apoptosis inhibitors activated by the TNFα-mediated NF-κB pathway. In conclusion, the FOXM1 gene may be a promising therapeutic target for ES.
上皮样肉瘤（ES）是一种罕见的侵袭性肉瘤，与大多数软组织肉瘤不同，它具有局部复发和淋巴结转移的倾向。需要为 ES 患者提供新型抗肿瘤药物。叉头框转录因子 1（FOXM1）是叉头转录因子家族的成员，与多种致癌功能相关；FOXM1 表达过度，与多种恶性肿瘤的发病机制相关。在这项研究中，我们通过免疫组织化学分析了 38 例 ES 标本中 FOXM1 的表达水平及其临床、临床病理和预后意义。此外，为了研究 FOXM1 下调与肿瘤特征之间的潜在相关性，我们用硫链丝菌素处理 ES 细胞系，硫链丝菌素是一种天然存在的抗生素，可同时抑制小干扰 RNA（siRNA）和 FOXM1。在使用 ES 样本的分析中，所有 38 个标本均通过免疫组化法被诊断为 FOXM1 阳性。我们通过染色指数评分将标本分为高（n=19）和低（n=19）FOXM1 蛋白表达组，并通过 5cm 最大直径的截点将标本分为大（n=12）、小（n=25）和未知（n=1）肿瘤大小组。尽管在大肿瘤组中具有高 FOXM1 表达的样本明显更多（P=0.013），但在年龄（P=1.00）、性别（P=0.51）、起源部位（P=0.74）、组织学亚型（P=1.00）、深度（P=0.74）或生存率（P=0.288）方面，高和低 FOXM1 蛋白表达组之间没有显著差异。在使用 ES 细胞系的体外实验中，FOXM1 siRNA 和硫链丝菌素成功下调了 FOXM1 mRNA 和蛋白表达。此外，下调 FOXM1 抑制了 ES 细胞系的细胞增殖、对化疗药物的耐药性、迁移和侵袭，并导致细胞周期停滞。最后，cDNA 微阵列分析数据表明，FOXM1 调节 cIAP2，cIAP2 是 TNFα 介导的 NF-κB 通路激活的凋亡抑制剂之一。总之，FOXM1 基因可能是 ES 的一个有前途的治疗靶点。
