目的探讨CDC5L在神经母细胞瘤(neuroblastoma,NB)中的表达及对患儿临床和预后的影响。方法免疫组化(immunohistochemistry,IHC)及蛋白免疫印迹(Western blot,WB)检测CDC5L在神经母细胞瘤患儿肿瘤组织中的表达,根据患儿性别、年龄、是否...目的探讨CDC5L在神经母细胞瘤(neuroblastoma,NB)中的表达及对患儿临床和预后的影响。方法免疫组化(immunohistochemistry,IHC)及蛋白免疫印迹(Western blot,WB)检测CDC5L在神经母细胞瘤患儿肿瘤组织中的表达,根据患儿性别、年龄、是否有骨髓浸润、肿瘤临床分期(INSS)、危险度分级、肿瘤病理诊断、Shimada病理分类及NSE、LDH是否正常进行分组,比较各组中CDC5L的表达差异,采用Kaplan-Meier和Cox回归分析CDC5L高表达组和低表达组对神经母细胞瘤生存的影响。结果IHC显示,62例神经母细胞瘤肿瘤标本中,CDC5L高表达及低表达各31例(50%),CDC5L主要在细胞核内表达;IHC及WB均显示CDC5L在神经母细胞瘤中的表达高于节细胞神经母细胞瘤(ganglioneuroblastoma,GNB), NB和GNB均起源于原始神经嵴细胞,可于肾上腺或沿脊柱旁交感神经节分布;不同之处在于NB较GNB分化差,恶性程度更高。进一步分析CDC5L在NB患儿临床和病理特征之间的表达差异发现肿瘤骨髓浸润组较无肿瘤浸润组CDC5L高表达的比例更高,差异有统计学意义(χ^2 =5.833, P =0.016);CDC5L在肿瘤临床分期Ⅲ~Ⅳ中的高表达比例高于Ⅰ~Ⅱ和Ⅳ-S期,差异有统计学意义(χ^2 =11.328, P =0.001);CDC5L高表达的比例在MYCN扩增组高于MYCN非扩增组( P =0.038);危险度分级中,高危患儿中CDC5L表达增高的比例较中危和低危患儿高(χ^ 2 =9.378, P =0.002 );Shimada病理分类中,不良组织学类型较良好组织学类型CDC5L表达增高的比例更高(χ^ 2 =7.839, P =0.005);NSE升高组较NSE正常组CDC5L表达增高的比例更高( P =0.035);LDH≥587 U/L较LDH<587 U/L有更高比例的CDC5L表达增高,差异有统计学意义(χ^ 2 =5.547, P = 0.019 )。Kaplan-Meier生存分析提示CDC5L高表达组3年存活率(48.8% vs. 88.0%)低于CDC5L低表达组,差异有统计学意义( P =0.002)。单因素Cox回归分析发现CDC5L高表达( HR =4.734,95% CI :1.590~ 14.091 )、临床分期为Ⅲ和Ⅳ期( HR =7.444,95% CI :2.187~25.339)、高危状态( HR = 2.749 ,95% CI :1.454~5.194)、Shimada 病理UFH型( HR =4.098,95% CI :1.493~11.250)均是NB患儿预后的危险因素。但是进一步多因素Cox回归分析发现上述因素均没有统计学差异( P > 0.05)结论CDC5L的表达和已知的患儿预后危险因素、不良病理类型及肿瘤标志物升高有较好的一致性,且生存分析也提示CDC5L高表达组较低表达组差,因此CDC5L可作为潜在的提示神经母细胞瘤患儿具有不良预后、不良病理类型和肿瘤标志物升高的分子标志物。展开更多
Multiple myeloma(MM)patients with chromosome 1q gain(1q+)are clinically and biologically heterogeneous.The underlying molecular mechanisms are still under investigation,while the identification of targets for effectiv...Multiple myeloma(MM)patients with chromosome 1q gain(1q+)are clinically and biologically heterogeneous.The underlying molecular mechanisms are still under investigation,while the identification of targets for effective therapy of this subgroup of MM patients is urgently needed.We aimed to investigate the clinical significance and the regulatory mechanisms of insulin-like growth factor 2 messenger RNA(mRNA)binding protein 1(IGF2BP1),a N6-methyladenosine(m6A)reader,in MM patients with 1q+.We found that MM patients with 1q+exhibit a significantly higher level of IGF2BP1 mRNA than controls,while higher IGF2BP1 expression predicted a worse prognosis in MM patients with 1q+.IGF2BP1 overexpression promoted cell proliferation and G1-to-S phase transition of the cell cycle in NCI-H929 cells.Through comprehensive in silico analyses of existing public datasets and in-house generated high-throughput sequencing datasets,along with in vitro experiments,we identified CDC5L as a target of IGFBP1,which can bind to the m6A sites of CDC5L mRNA to up-regulate its protein abundance.Higher CDC5L expression also predicted a worse prognosis of MM patients with 1q+.Moreover,both knockdown and mutation of CDC5L attenuated the pro-proliferative effect of IGF2BP1.Furthermore,IGF2BP1 inhibitor BTYNB effectively inhibited CDC5L expression in MM cells with 1q+and suppressed the proliferation of these cells in vitro and in vivo.Therefore,IGF2BP1 acts as a post-transcriptional enhancer of CDC5L in an m6A-dependent manner to promote the proliferation of MM cells with 1q+.Our work identified a novel IGF2BP1-CDC5L axis and provided new insight into developing targeted therapeutics for MM patients with 1q+.展开更多
文摘目的探讨CDC5L在神经母细胞瘤(neuroblastoma,NB)中的表达及对患儿临床和预后的影响。方法免疫组化(immunohistochemistry,IHC)及蛋白免疫印迹(Western blot,WB)检测CDC5L在神经母细胞瘤患儿肿瘤组织中的表达,根据患儿性别、年龄、是否有骨髓浸润、肿瘤临床分期(INSS)、危险度分级、肿瘤病理诊断、Shimada病理分类及NSE、LDH是否正常进行分组,比较各组中CDC5L的表达差异,采用Kaplan-Meier和Cox回归分析CDC5L高表达组和低表达组对神经母细胞瘤生存的影响。结果IHC显示,62例神经母细胞瘤肿瘤标本中,CDC5L高表达及低表达各31例(50%),CDC5L主要在细胞核内表达;IHC及WB均显示CDC5L在神经母细胞瘤中的表达高于节细胞神经母细胞瘤(ganglioneuroblastoma,GNB), NB和GNB均起源于原始神经嵴细胞,可于肾上腺或沿脊柱旁交感神经节分布;不同之处在于NB较GNB分化差,恶性程度更高。进一步分析CDC5L在NB患儿临床和病理特征之间的表达差异发现肿瘤骨髓浸润组较无肿瘤浸润组CDC5L高表达的比例更高,差异有统计学意义(χ^2 =5.833, P =0.016);CDC5L在肿瘤临床分期Ⅲ~Ⅳ中的高表达比例高于Ⅰ~Ⅱ和Ⅳ-S期,差异有统计学意义(χ^2 =11.328, P =0.001);CDC5L高表达的比例在MYCN扩增组高于MYCN非扩增组( P =0.038);危险度分级中,高危患儿中CDC5L表达增高的比例较中危和低危患儿高(χ^ 2 =9.378, P =0.002 );Shimada病理分类中,不良组织学类型较良好组织学类型CDC5L表达增高的比例更高(χ^ 2 =7.839, P =0.005);NSE升高组较NSE正常组CDC5L表达增高的比例更高( P =0.035);LDH≥587 U/L较LDH<587 U/L有更高比例的CDC5L表达增高,差异有统计学意义(χ^ 2 =5.547, P = 0.019 )。Kaplan-Meier生存分析提示CDC5L高表达组3年存活率(48.8% vs. 88.0%)低于CDC5L低表达组,差异有统计学意义( P =0.002)。单因素Cox回归分析发现CDC5L高表达( HR =4.734,95% CI :1.590~ 14.091 )、临床分期为Ⅲ和Ⅳ期( HR =7.444,95% CI :2.187~25.339)、高危状态( HR = 2.749 ,95% CI :1.454~5.194)、Shimada 病理UFH型( HR =4.098,95% CI :1.493~11.250)均是NB患儿预后的危险因素。但是进一步多因素Cox回归分析发现上述因素均没有统计学差异( P > 0.05)结论CDC5L的表达和已知的患儿预后危险因素、不良病理类型及肿瘤标志物升高有较好的一致性,且生存分析也提示CDC5L高表达组较低表达组差,因此CDC5L可作为潜在的提示神经母细胞瘤患儿具有不良预后、不良病理类型和肿瘤标志物升高的分子标志物。
基金supported by the National Natural Science Foundation of China(No.82100215)Natural Science Foundation of Shanghai,China(No.22ZR1411400)Natural Science Foundation of Fujian Province,China(No.2023J05291).
文摘Multiple myeloma(MM)patients with chromosome 1q gain(1q+)are clinically and biologically heterogeneous.The underlying molecular mechanisms are still under investigation,while the identification of targets for effective therapy of this subgroup of MM patients is urgently needed.We aimed to investigate the clinical significance and the regulatory mechanisms of insulin-like growth factor 2 messenger RNA(mRNA)binding protein 1(IGF2BP1),a N6-methyladenosine(m6A)reader,in MM patients with 1q+.We found that MM patients with 1q+exhibit a significantly higher level of IGF2BP1 mRNA than controls,while higher IGF2BP1 expression predicted a worse prognosis in MM patients with 1q+.IGF2BP1 overexpression promoted cell proliferation and G1-to-S phase transition of the cell cycle in NCI-H929 cells.Through comprehensive in silico analyses of existing public datasets and in-house generated high-throughput sequencing datasets,along with in vitro experiments,we identified CDC5L as a target of IGFBP1,which can bind to the m6A sites of CDC5L mRNA to up-regulate its protein abundance.Higher CDC5L expression also predicted a worse prognosis of MM patients with 1q+.Moreover,both knockdown and mutation of CDC5L attenuated the pro-proliferative effect of IGF2BP1.Furthermore,IGF2BP1 inhibitor BTYNB effectively inhibited CDC5L expression in MM cells with 1q+and suppressed the proliferation of these cells in vitro and in vivo.Therefore,IGF2BP1 acts as a post-transcriptional enhancer of CDC5L in an m6A-dependent manner to promote the proliferation of MM cells with 1q+.Our work identified a novel IGF2BP1-CDC5L axis and provided new insight into developing targeted therapeutics for MM patients with 1q+.
