Tumor-biological significance of Myc-relarted gene products in neuroblastoma cells

神经母细胞瘤细胞中 Myc 相关基因产物的肿瘤生物学意义

• 批准号: 10670749
• 负责人: HOSOI Hajime
• 金额: $ 2.05万
• 依托单位: Kyoto Prefectural University of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670749/
• 关键词: neuroblastoma; N-myc; retinoic acid; differentiation; IGF-I; MAPK; 神経芽細胞腫; mycN; mxi1; max; レチノイン酸誘導体; 細胞周期

Insulin-like growth factor I (IGF-I) stimulates proliferation, survival and differentiation in many cell types, including the pediatric neuroblastomas. The effect is mediated via the type I IGF-I receptor (IGF-IR), which is essential for growth in these cells. Several lines of evidence indicated that IGF-IR function may be particular important in the pathogenesis of the neuroblastoma. Amplification of the N-myc oncogene or overexpression of N-Myc oncoprotein have been reported to be associated with resistance to therapy and poor prognosis of neuroblastomas. It was therefore of interest to analyze whether IGF-I signaling regulated expression on N-myc in KP-N-RT human neuroblastoma cells as an experimental model that has amplified N-myc. We found that IGF-I induces N-myc mRNA and protein in the KP-N-RT with the maximum of 4 and 6 times more than the basal level at 2 and 3 hrs after the stimulation, respectively. These effects of IGF-I were blocked by a neutralizing antibody against IGF-IR (α-IR3). Exogenous IGF-I induced phosphorylation of extracellular signal-regulated kinases p42/44 (Erk1 and Erk2), with a maximal level 30 min after the stimulation. The MEK1 inhibitor PD98059 reduced IGF-I-mediated p42/44 tyrosine phosphorylation, and produced a parallel reduction of IFG-I-stimulated N-Myc induction. Furthermore, both α-IR3 and PD98059 inhibited G1-S cell cycle progression stimulated by IGF-I. Our results demonstrate that IGF-I induces N-Myc in the KP-N-RT neuroblastoma cell line at the RNA level and establishes a clear correlation between N-Myc induction and activation of p42/44 MAPK signaling.

胰岛素样生长因子I（IGF-I）刺激许多细胞类型的增殖，存活和分化，包括小儿神经母细胞瘤。该作用是通过I型IGF-I受体（IGF-IR）介导的，该受体对于这些细胞的生长至关重要。几条证据表明，IGF-IR功能在神经母细胞瘤的发病机理中尤为重要。据报道，N-myc癌基因的扩增或N-Myc癌蛋白的过表达与对治疗的耐药性和神经母细胞瘤预后不良有关。因此，要分析IGF-I信号传导在KP-N-RT人类神经母细胞瘤细胞中是否对N-MYC的表达进行调节，作为已扩展N-MYC的实验模型。我们发现，IGF-I在KP-N-RT中影响N-MYC mRNA和蛋白质，刺激后2和3小时的基本水平分别比基本水平高4和6倍。 IGF-I的这些作用通过对IGF-IR（α-IR3）的中和抗体阻断。外源IGF-I诱导细胞外信号调节激酶P42/44（ERK1和ERK2）的磷酸化，刺激后30分钟最大水平。 MEK1抑制剂PD98059降低了IGF-I介导的P42/44酪氨酸磷酸化，并产生了IFG-I刺激的N-MYC诱导的平行降低。此外，α-IR3和PD98059均抑制了IGF-I刺激的G1-S细胞周期进程。我们的结果表明，在RNA水平的KP-N-RT神经母细胞瘤细胞系中的IGF-I在N-MYC诱导与P42/44 MAPK信号的激活之间建立了明显的相关性。

项目成果

Dias P,Hosoi H: "Strong immunostaining for myogenin in rhabdomyosarcoma is significantly associated with tumors of alveolar subclass"Am J Pathol. 156. 399-408 (2000)

Dias P，Hosoi H：“横纹肌肉瘤中肌细胞生成素的强免疫染色与肺泡亚类肿瘤显着相关”Am J Pathol。

Hajime Hosoi: "Kinetics of rapamycin-induced p53-independent apoptosis in human rhabdomyosarcoma cells." Cancer Research. 59・4. 886-894 (1999)

Hajime Hosoi：“雷帕霉素诱导的人横纹肌肉瘤细胞中不依赖于 p53 的细胞凋亡的动力学。”59·4（1999）。

Hosoi H,: "Rapamycin causes poorly rcversible inhibition of in TOR and induces p53-indcpecudent apoptosis in human rbabdowyosarco** cells"Cancer Res. 59・4. 886-894 (1999)

Hosoi H，：“雷帕霉素导致 TOR 的可逆抑制，并诱导人 rbabdowyosarco** 细胞中 p53 相关的细胞凋亡”Cancer Res 59·4 (1999)。

Hosoi H,: "Rapamycin causes poorly reversible inhibitior of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells"Cancer Res. 59. 886-894 (1999)

Hosoi H，：“雷帕霉素导致 mTOR 的可逆性较差的抑制，并诱导人横纹肌肉瘤细胞中不依赖于 p53 的细胞凋亡”Cancer Res。

Sugimoto T,Hosoi H: "Malignant rhabdoid-tumor cells line showing neural and smooth-muscle-cell phenotypes"Int J Cancer. 82. 678-686 (1999)

Sugimoto T，Hosoi H：“显示神经和平滑肌细胞表型的恶性横纹肌瘤细胞系”Int J Cancer。