Phi Ji Hoon, Choi Seung-Ah, Kim Seung-Ki, Wang Kyu-Chang, Lee Ji Yeoun, Kim Dong Gyu
Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul, Republic of Korea; Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Neurosurgery, Seoul National University Hospital, Seoul, Republic of Korea; Seoul National University College of Medicine, Seoul, Republic of Korea.
Transl Oncol. 2015 Oct;8(5):376-386. doi: 10.1016/j.tranon.2015.08.001.
The long-term clinical outcome of pediatric intracranial epepdymoma is poor with a high rate of recurrence. One of the main reasons for this poor outcome is the tumor's inherent resistance to chemotherapy. Signal transducer and activator of transcription 3 (STAT3) is overactive in many human cancers, and inhibition of STAT3 signaling is an emerging area of interest in oncology. In this study, the possibility of STAT3 inhibition as a treatment was investigated in pediatric intracranial ependymoma tissues and cell lines. STAT3 activation status was checked in ependymoma tissues. The responses to conventional chemotherapeutic agents and a STAT3 inhibitor WP1066 in primarily cultured ependymoma cells were measured by cell viability assay. Apoptosis assays were conducted to reveal the cytotoxic mechanism of applied agents. Knockdown of STAT3 was tried to confirm the effects of STAT3 inhibition in ependymoma cells. High levels of phospho-STAT3 (p-STAT3) expression were observed in ependymoma tissue, especially in the anaplastic histology group. There was no cytotoxic effect of cisplatin, ifosfamide, and etoposide. Both brain tumor-initiating cells (BTICs) and bulk tumor cells (BCs) showed considerably decreased viability after WP1066 treatment. However, BTICs had fewer responses than BCs. No additive or synergistic effect was observed for combination therapy of WP1066 and cisplatin. WP1066 effectively abrogated p-STAT3 expression. An increased apoptosis and decreased Survivin expression were observed after WP1066 treatment. Knockdown of STAT3 also decreased cell survival, supporting the critical role of STAT3 in sustaining ependymoma cells. In this study, we observed a cytotoxic effect of STAT3 inhibitor on ependymoma BTICs and BCs. There is urgent need to develop new therapeutic agents for pediatric ependymoma. STAT3 inhibitors may be a new group of drugs for clinical application.
小儿颅内室管膜瘤的长期临床预后较差，复发率很高。导致这种不良预后的主要原因之一是肿瘤对化疗具有内在抗性。信号转导和转录激活因子3（STAT3）在许多人类癌症中过度活跃，抑制STAT3信号传导是肿瘤学中一个新兴的研究领域。在本研究中，研究了抑制STAT3作为小儿颅内室管膜瘤组织和细胞系治疗方法的可能性。检测了室管膜瘤组织中STAT3的激活状态。通过细胞活力测定法测量原代培养的室管膜瘤细胞对传统化疗药物和STAT3抑制剂WP1066的反应。进行凋亡检测以揭示所用药物的细胞毒性机制。尝试敲低STAT3以证实抑制STAT3对室管膜瘤细胞的作用。在室管膜瘤组织中观察到高水平的磷酸化STAT3（p-STAT3）表达，尤其是在间变性组织学组中。顺铂、异环磷酰胺和依托泊苷没有细胞毒性作用。脑肿瘤起始细胞（BTICs）和大量肿瘤细胞（BCs）在WP1066处理后活力均显著降低。然而，BTICs的反应比BCs少。WP1066和顺铂联合治疗未观察到相加或协同作用。WP1066有效地消除了p-STAT3的表达。WP1066处理后观察到凋亡增加和生存素表达降低。敲低STAT3也降低了细胞存活率，支持了STAT3在维持室管膜瘤细胞中的关键作用。在本研究中，我们观察到STAT3抑制剂对室管膜瘤BTICs和BCs具有细胞毒性作用。迫切需要开发针对小儿室管膜瘤的新治疗药物。STAT3抑制剂可能是一类新的临床应用药物。
