APAF-1 is related to an undifferentiated state in the testicular germ cell tumor pathway
APAF-1 is related to an undifferentiated state in the testicular germ cell tumor pathway
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APAF-1 与睾丸生殖细胞肿瘤途径的未分化状态相关
DOI：
10.1111/j.1349-7006.2010.01750.x
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发表时间：
2011
期刊：
影响因子：
5.7
通讯作者：
et al.
中科院分区：
文献类型：
--
作者：
Behjati R;Kano J;Noguchi M;et al.
凋亡蛋白酶激活因子- 1 （APAF - 1）是凋亡的关键调控基因，位于mp53的下游。apaf‐1表达的缺失与化疗难治性恶性黑色素瘤和神经元细胞分化有关。为了明确APAF‐1在生殖细胞肿瘤的癌变过程中的作用，我们采用免疫组化的方法检测了43例睾丸生殖细胞肿瘤（TGCT）和6例正常睾丸组织的福尔马林固定石蜡包埋标本中APAF‐1和几种凋亡和分化标志物的表达水平。通过免疫组织化学检测cleaved caspase‐3、Oct‐3/4和Ki‐67的表达，分别评估凋亡反应性、肿瘤分化和增殖活性。通过siRNA转染，在两个TGCT细胞系中下调APAF‐1，随后检测ki‐67和doct‐3/4基因的表达以及三个胚胎胚层的分化标记，包括外胚层的角化蛋白16 (KRT16)，中胚层的vimentin （VIM）和内胚层的gata4。在tgct中APAF‐1的表达与凋亡活性之间没有明显的关系。APAF‐1、Oct‐3/4和Ki‐67在精原细胞瘤中的表达明显高于非精原细胞瘤。在tgct中，较高的APAF‐1表达与较高的增殖（高Ki‐67）和较低的分化程度（高Oct‐3/4）相关。有趣的是，APAF‐1的表达随着肿瘤分化（精原细胞瘤和胚胎癌>畸胎瘤）而逐渐降低。在TGCT细胞系中，apaf‐1的下调导致ki‐67和doct‐3/4的降低，以及vimand krt16基因表达的增加。这些数据表明，在TGCT通路中，apaf‐1的高表达与未分化状态有关。（癌症科学2011；02:267-274）
Apoptotic protease activating factor‐1 (APAF‐1) is a key regulator gene of apoptosis, located downstream fromp53. Loss ofAPAF‐1expression is associated with chemorefractory malignant melanoma and neuronal cell differentiation. In order to make clear the function of APAF‐1 in the carcinogenesis of germ cell tumors, we evaluated the expression levels of APAF‐1 and several apoptosis and differentiation markers by immunohistochemistry in formalin‐fixed paraffin‐embedded samples from 43 cases of testicular germ cell tumor (TGCT) and six specimens of normal testis tissue. Expression of cleaved caspase‐3, Oct‐3/4, and Ki‐67 were also examined by immunohistochemistry to evaluate apoptotic reactivity, tumor differentiation, and proliferation activity, respectively.APAF‐1was downregulated in two TGCT cell lines by siRNA transfection, and subsequent expression of theKi‐67andOct‐3/4genes and differentiation markers of three embryonic germ layers includingkeratin16 (KRT16)for ectoderm,vimentin (VIM)for mesoderm andGATA4for endoderm were then tested. No significant relationship was found between APAF‐1 expression and apoptotic activity in TGCTs. Expression of APAF‐1, Oct‐3/4, and Ki‐67 was significantly higher in seminomas than in non‐seminomas. In TGCTs, higher APAF‐1 expression was correlated with higher proliferation (high Ki‐67) and a lower degree of differentiation (high Oct‐3/4). Interestingly, the expression of APAF‐1 gradually decreased in accordance with tumor differentiation (seminoma and embryonal carcinoma > teratoma). Downregulation ofAPAF‐1in TGCT cell lines resulted in a decrease ofKi‐67andOct‐3/4and an increase ofVIMandKRT16gene expression. These data show that higher expression ofAPAF‐1is related to an undifferentiated state in the TGCT pathway. (Cancer Sci2011; 102: 267–274)