HIF-1α/SHH信号通路在神经母细胞瘤中的表达及临床意义

Expression and clinical significance of HIF-1α/SHH signaling pathway in neuroblastoma

目的·探讨低氧诱导因子1α(hypoxia inducible factor-1α,HIF-1α)和音猬因子(sonic hedgehog,SHH)在神经母细胞瘤(neuroblastoma,NB)中的表达及临床意义。方法·采用免疫组织化学SP(streptavdin-peroxidase)法分析101例NB和20例节细胞神经瘤(ganglioneuroma,GN)患儿肿瘤组织石蜡切片中HIF-1α、SHH的表达水平,比较两者在NB、GN中表达水平的差异,并分析HIF-1α、SHH表达水平与NB患儿临床病理特征以及预后的相关性。结果·HIF-1α、SHH在NB中的表达水平高于GN(HIF-1α:26.7%vs 5.0%,P=0.035;SHH:32.7%vs 10.0%,P=0.041)。相比低分期(1、2期)、组织分化良好的NB,HIF-1α、SHH在高分期(3、4期)、组织分化不良的NB中表达水平更高(HIF-1α:P值分别为0.002、0.012;SHH:P值分别为0.021、0.007)。有局部淋巴结转移的NB中,这2种蛋白的表达水平也更高(HIF-1α:P=0.012;SHH:P=0.001)。NB中HIF-1α、SHH的表达水平呈显著正相关(r=0.41,P=0.000),HIF-1α高表达组的5年总体生存(overall survival,OS)率和无事件生存(event-free survival,EFS)率低于HIF-1α低表达组,差异有统计学意义(OS率:40.9%vs 75.7%,P=0.001;EFS率:40.9%vs 70.0%,P=0.008)。SHH高表达组的5年OS率、EFS率也低于SHH低表达组,差异有统计学意义(OS率:42.9%vs 78.1%,P=0.000;EFS率:39.3%vs 73.4%,P=0.001)。结论·HIF-1α、SHH的高表达与NB高分期、局部淋巴结转移和组织结构不良的病理分型等临床特征密切相关,并预示NB患儿的不良预后;HIF-1α/SHH信号通路可能是NB潜在的生物标志物和治疗靶点。

Objective·To investigate the expression and clinical significance of hypoxia inducible factor-1α(HIF-1α)/sonic hedgehog(SHH)signaling pathway in neuroblastoma(NB).Methods·The expressions of HIF-1αand SHH in paraffin sections of 101 NB cases and 20 ganglioneuroma(GN)cases were analyzed by immunohistochemistry.The differences in the expression levels of these two proteins were compared between NB and GN.And correlations between HIF-1α/SHH expression levels and NB patients′clinicopathological characteristics or prognosis were analyzed.Results·The expression levels of HIF-1αand SHH in NBs were significantly higher than those in GNs(HIF-1α:26.7%vs 5.0%,P=0.035;SHH:32.7%vs 10.0%,P=0.041).Compared with low-stage(stage 1 and 2)NBs or NBs with favorable histology,HIF-1αand SHH expression levels were significantly higher in high-stage(stage 3 and 4)NBs or NBs with unfavorable histology(HIF-1α:P=0.002 and 0.012,respectively;SHH:P=0.021 and 0.007,respectively).The expression levels of these two proteins were also higher in NBs with local lymph node metastasis(HIF-1α:P=0.012;SHH:P=0.001).A significant positive correlation was found between HIF-1αand SHH expression levels in NB specimens(r=0.41,P=0.000).The 5-year overall survival(OS)rate and event-free survival(EFS)rate of the HIF-1αhigh-expression group were significantly lower than those of the HIF-1αlow-expression group(OS rate:40.9%vs 75.7%,P=0.001;EFS rate:40.9%vs 70.0%,P=0.008).The 5-year OS rate and EFS rate of the SHH high-expression group were also significantly lower than those of the SHH low-expression group(OS rate:42.9%vs 78.1%,P=0.000;EFS rate:39.3%vs 73.4%,P=0.001).Conclusion·The increased expressions of HIF-1αand SHH in NB are closely related to clinical features of NB,such as stage,local lymph node metastasis and unfavorable histology,and indicate the poor prognosis.Hence,HIF-1α/SHH signal pathway might be a potential biomarker and therapeutic target for NB.