Gene expression profiling of advanced-stage serous ovarian cancers distinguishes novel subclasses and implicates ZEB2 in tumor progression and prognosis
Gene expression profiling of advanced-stage serous ovarian cancers distinguishes novel subclasses and implicates ZEB2 in tumor progression and prognosis
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DOI：
10.1111/j.1349-7006.2009.01204.x
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发表时间：
2009-08-01
期刊：
影响因子：
5.7
通讯作者：
Tanaka, Kenichi
中科院分区：
文献类型：
--
作者：
Yoshihara, Kosuke;Tajima, Atsushi;Tanaka, Kenichi
为探讨浆液性卵巢癌快速进展的机制，应用包含18716个基因的寡核苷酸芯片，对43例卵巢癌组织（包括8例早期卵巢癌和35例晚期卵巢癌）进行了基因表达谱分析。通过非负矩阵因子分析，使用178个基因，提取的阶段特异性基因，35例晚期病例分为两个亚类与上级（n = 17）和差（n = 18）的无进展生存期评估（对数秩检验，P = 0.03）的结果。在178个阶段特异性基因中，112个基因被鉴定为在两个亚类之间显示出不同的表达。在通过基因本体分析或免疫途径分析选择用于生物学功能的48个基因中，提取5个基因（ZEB 2、CDH 1、LTBP 2、COL 16 A1和ACTA 2）作为与无进展生存期相关的预后因子的候选者。通过对37例独立的晚期癌症样本进行实时RT-PCR实验，验证了高ZEB 2或低CDH 1表达与较短无进展生存期之间的关系。在晚期样本中，ZEB 2表达与CDH 1表达呈负相关，而在卵巢腺癌SKOV 3细胞中ZEB 2敲低导致CDH 1表达增加。多因素分析显示ZEB 2高表达与预后不良独立相关。此外，使用独立的晚期癌症样本集（n = 74）的免疫组化分析验证了由CDH 1编码的E-钙粘蛋白的预后作用。这些结果表明，上皮间质转化相关基因如ZEB 2和CDH 1的表达可能在晚期浆液性卵巢癌的侵袭过程中起重要作用。（Cancer Sci 2009）。
To elucidate the mechanisms of rapid progression of serous ovarian cancer, gene expression profiles from 43 ovarian cancer tissues comprising eight early stage and 35 advanced stage tissues were carried out using oligonucleotide microarrays of 18 716 genes. By non-negative matrix factorization analysis using 178 genes, which were extracted as stage-specific genes, 35 advanced stage cases were classified into two subclasses with superior (n = 17) and poor (n = 18) outcome evaluated by progression-free survival (log rank test, P = 0.03). Of the 178 stage-specific genes, 112 genes were identified as showing different expression between the two subclasses. Of the 48 genes selected for biological function by gene ontology analysis or Ingenuity Pathway Analysis, five genes (ZEB2, CDH1, LTBP2, COL16A1, and ACTA2) were extracted as candidates for prognostic factors associated with progression-free survival. The relationship between high ZEB2 or low CDH1 expression and shorter progression-free survival was validated by real-time RT-PCR experiments of 37 independent advanced stage cancer samples. ZEB2 expression was negatively correlated with CDH1 expression in advanced stage samples, whereas ZEB2 knockdown in ovarian adenocarcinoma SKOV3 cells resulted in an increase in CDH1 expression. Multivariate analysis showed that high ZEB2 expression was independently associated with poor prognosis. Furthermore, the prognostic effect of E-cadherin encoded by CDH1 was verified using immunohistochemical analysis of an independent advanced stage cancer samples set (n = 74). These findings suggest that the expression of epithelial-mesenchymal transition-related genes such as ZEB2 and CDH1 may play important roles in the invasion process of advanced stage serous ovarian cancer. (Cancer Sci 2009).