The roles of hASH1 gone in neuroendocrine differentiation of lung cancer and in the development of the lung

应用原位杂交技术检测238例手术切除的肺癌组织中hASH 1 mRNA的表达，并分析其与神经内分泌标志物、肽类激素表达及临床预后的关系。hASH 1表达仅限于具有神经内分泌表型的肿瘤。然而，并非所有神经内分泌肿瘤都表达hASH 1，hASH 1的表达与嗜铬粒蛋白A、胃泌素释放肽和降钙素密切相关（P<0.0001，r=0.852），但与神经细胞粘附表达无关（P=0.8892），表明hASH 1表达，至少在肺癌中，与广义上的“神经内分泌分化”以外的内分泌表型表达相关。hASH 1在几乎完全分化的典型类癌（TC）中几乎不存在，但在大多数（如果不是全部的话）低分化的非典型类癌（ATC）以及大细胞神经内分泌癌（LCNEC）和小细胞肺癌（NSCLC）中表达。 ...更多信息 小细胞肺癌（SCLC）的研究表明，hASH 1在肺癌中的表达模仿其在胎儿发育中的早期和瞬时表达，并且hASH 1有助于细胞内分泌表型的建立，但不是维持细胞内分泌表型。最后，hASH 1表达与SCLC患者生存期显著缩短相关（P=0.041）。我们还研究了细胞周期蛋白B1表达失调和Rb/p16/细胞周期蛋白D1通路（Rb通路）的破坏，并将结果与肿瘤增殖活性和临床结局相关。细胞周期蛋白B1相关的G2/M期阻滞和Rb介导的G1期阻滞在高级别LCNEC和SCLC中始终受到损害，但在TC/ATC中通常是完整的或偶尔改变; Rb通路畸变的机制在肿瘤类别中是不同的。Cyclin B1表达与Ki-67标记指数在各肿瘤类型中密切相关（P<0.0001，r=0.742），提示cyclin B1在调节细胞增殖中起关键作用。无论是细胞周期蛋白B1和D1，Rb，p16，也没有Ki-67与患者的生存在个别肿瘤类别。少

hASH1 mRNA expression was investigated by in situ hybridization in 238 surgically resected lung carcinomas, and the correlations between hASH1 expression and general neuroendocrine marker and peptide hormone expression as well as clinical outcome were analyzed. hASH1 expression was restricted to tumors with neuroendocrine phenotypes. However, not all neuroendocrine tumors expressed hASH1 and hASH1 expression correlated closely with chromogranin A, gastrin-releasing peptide and calcitonin (P<0.0001, r=0.852), but was not related to neural cell adhesion expression (P=0.8892), suggesting that hASH1 expression, at least in lung cancer, is associated with endocrine phenotype expression other than 'neuroendocrine differentiation' in a broad sense. That hASH1 was virtually absent in almost fully differentiated typical carcinoids (TC), but was expressed in most, if not all, less differentiated atypical carcinoids (ATC) as well as large-cell neuroendocrine carcinoma (LCNEC) and small cell lung … More carcinoma (SCLC), suggests that hASH1 expression in lung cancer imitates its early and transient expression in fetal development, and that hASH1 is instrumental in the establishment, but not in the maintenance, of a cellular endocrine phenotype. Finally, hASH1 expression correlated with a significantly shortened survival in SCLC patients (P=0.041).Dysregulated cyclin B1 expression and disruption of the Rb/p16/cyclin D1 pathway (Rb pathway) were also studied, and the results were correlated with tumor proliferation activity and clinical outcome. Both cyclin B1-associated G2/M arrest and Rb-mediated G1 arrest are consistently compromised in high-grade LCNEC and SCLC, but are generally intact or occasionally altered in TC/ATC ; and the mechanisms involved in Rb pathway aberration among the tumor categories are different. Cyclin B1 expression closely correlated with the Ki-67 labeling index in each tumor category (P<0.0001, r=0.742), suggesting a key role for cyclin B1 in regulating cell proliferation. Neither cyclins B1 and D1, Rb, p16, nor Ki-67 correlated with patient survival in individual tumor categories. Less