Chikaraishi Koji, Takenobu Hisanori, Sugino Ryuichi P, Mukae Kyosuke, Akter Jesmin, Haruta Masayuki, Kurosumi Masafumi, Endo Takaho A, Koseki Haruhiko, Shimojo Naoki, Ohira Miki, Kamijo Takehiko
Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan.
Department of Pediatrics, Chiba University, Chiba, Japan.
Oncotarget. 2017 Jul 11;8(28):45046-45059. doi: 10.18632/oncotarget.18464.
Despite the use of aggressive therapy, survival rates among high-risk neuroblastoma (NB) patients remain poor. Cancer stem cells (CSCs) are considered to be critically involved in the recurrence and metastasis of NB and are isolated as NB spheres.
The gene expression profiling of adherent (control) and sphere-forming primary NB cells was conducted using a gene expression microarray. CFC1, which functions in the development of embryos and decides the left-right axis, was strongly expressed in sphere-forming cells only and was related to the unfavorable prognosis of NB patients. The knockdown and overexpression of CFC1 were performed using a lentiviral system in NB cell lines. Sphere formation, cell proliferation, colony formation in soft agar, and xenograft tumor formation were analyzed.
The overexpression of CFC1 increased sphere formation, cell growth, and colony formation. These phenotypes, particularly sphere formation, and xenograft tumor formation were significantly suppressed by the knockdown of CFC1. CFC1 inhibited Activin A-induced NB cell differentiation and Smad2 phosphorylation in NB cell lines, indicating its involvement in tumorigenesis related to EGF-CFC co-receptor family molecule pathways. Collectively, these results indicate that CFC1 is a candidate molecule for the development of CSC-targeted therapy for NB.
尽管采用了积极的治疗方法，但高危神经母细胞瘤（NB）患者的生存率仍然很低。癌症干细胞（CSCs）被认为与NB的复发和转移密切相关，并被分离为NB球。
使用基因表达微阵列对贴壁（对照）和形成球的原代NB细胞进行基因表达谱分析。CFC1在胚胎发育中起作用并决定左右轴，仅在形成球的细胞中强烈表达，并且与NB患者的不良预后相关。在NB细胞系中使用慢病毒系统进行CFC1的敲低和过表达。分析了球形成、细胞增殖、软琼脂中的集落形成和异种移植肿瘤形成。
CFC1的过表达增加了球形成、细胞生长和集落形成。这些表型，特别是球形成和异种移植肿瘤形成，通过CFC1的敲低得到显著抑制。CFC1抑制激活素A诱导的NB细胞系中的NB细胞分化和Smad2磷酸化，表明其参与与EGF-CFC共受体家族分子途径相关的肿瘤发生。总体而言，这些结果表明CFC1是NB的CSC靶向治疗开发的候选分子。
