Insulin-like growth factor II is involved in the proliferation control of medulloblastoma and its cerebellar precursor cells
Insulin-like growth factor II is involved in the proliferation control of medulloblastoma and its cerebellar precursor cells
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DOI：
10.1016/s0002-9440(10)62335-8
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发表时间：
2005-04-01
影响因子：
6
通讯作者：
Pietsch, T
中科院分区：
文献类型：
--
作者：
Hartmann, W;Koch, A;Pietsch, T
髓母细胞瘤是儿童最常见的恶性脑肿瘤，可能起源于小脑神经前体细胞。胰岛素样生长因子H（IGF-II）是参与不同胚胎性肿瘤发病机制的一种重要的胎儿有丝分裂原。我们筛选人MB活检的经典（CMB）和促结缔组织增生（DMB）的IGF 2转录的四个IGF 2启动子的变体。我们发现IGF 2转录从印记启动子P3显着增加促结缔组织增生的变异相比，经典的亚组。这不是促结缔组织增生性肿瘤中IGF 2印迹丢失的结果。接下来，我们检查了IGF-II和Sonic hedgehog（Shh）的相互作用，Shh是外部颗粒细胞层中小脑颗粒细胞前体（GCPs）的关键有丝分裂原，据信DMB就是从外部颗粒细胞层起源的。编码Shh-补丁信号通路组分的基因突变发生在类似于50%的DMB中。为了分析IGF-II对Hedgehog信号传导的影响，我们在Shh和IGF-II存在下培养鼠GCP和人NIB细胞。在GCPs中，Shh和Igf-II对增殖和gli 1和cyclin D1 mRNA表达有协同作用，Igf-II诱导Akt及其下游靶点Gsk-3 β磷酸化，而Shh不诱导。在9个人MB细胞系中的6个中，IGF-II显示出主要通过IGF-I受体介导的生长促进作用。总之，我们的数据点的重要作用IGF-II的小脑神经前体细胞和MB细胞的增殖控制。
Medulloblastomas (MBs), the most frequent malignant brain tumors of childhood, presumably originate from cerebellar neural precursor cells. An essential fetal mitogen involved in the pathogenesis of different embryonal tumors is insulin-like growth factor H (IGF-II). We screened human MB biopsies of the classic (CMB) and desmoplastic (DMB) variants for IGF2 transcripts of the four IGF2 promoters. We found IGF2 transcription from the imprinted promoter P3 to be significantly increased in the desmoplastic variant compared to the classic subgroup. This was not a result of loss of imprinting of IGF2 in desmoplastic tumors. We next ex amined the interaction of IGF-II and Sonic hedgehog (Shh), which serves as a critical mitogen for cerebellar granule cell precursors (GCPs) in the external granule cell layer from which DMBs are believed to originate. Mutations of genes encoding components of the Shh-Patched signaling pathway occur in similar to 50% of DMBs. To analyze the effects of IGF-II on Hedgehog signaling, we cultured murine GCP and human NIB cells in the presence of Shh and Igf-II. In GCPs, a synergistic effect of Shh and Igf-II on proliferation and gli1 and cyclin D1 mRNA expression was found. Igf-II, but not Shh, induced phosphorylation of Akt and its downstream target Gsk-3 beta. In six of nine human MB cell lines IGF-II displayed a growth promoting effect that was mediated mainly through the IGF-I receptor. Together, our data point to an important role of IGF-II for the proliferation control of both cerebellar neural precursors and MB cells.