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。这种作用是通过I型IGF-I受体（IGF-IR）介导的，IGF-IR对这些细胞的生长至关重要。一些证据表明，IGF-IR功能可能是特别重要的神经母细胞瘤的发病机制。N-myc癌基因的扩增或N-Myc癌蛋白的过表达已被报道与成神经细胞瘤的治疗抗性和不良预后相关。因此，分析IGF-I信号传导是否调节KP-N-RT人神经母细胞瘤细胞中N-myc的表达作为扩增N-myc的实验模型是有意义的。我们发现IGF-I诱导KP-N-RT中N-myc mRNA和蛋白的表达，在刺激后2和3小时分别达到最大值，为基础水平的4倍和6倍。IGF-I的这些作用可被抗IGF-IR的中和抗体（α-IR 3）阻断。外源性IGF-I诱导细胞外信号调节激酶p42/44（Erk 1和Erk 2）磷酸化，刺激后30分钟达到最高水平。MEK 1抑制剂PD 98059减少IGF-I介导的p42/44酪氨酸磷酸化，并产生IFG-I刺激的N-Myc诱导的平行减少。此外，α-IR 3和PD 98059均能抑制IGF-I刺激的G1-S期细胞进程。我们的研究结果表明，IGF-I在RNA水平诱导KP-N-RT神经母细胞瘤细胞系中的N-Myc，并建立了N-Myc诱导和p42/44 MAPK信号转导激活之间的明确相关性。

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。

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)。

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 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。