Kim Hyeyeung, Wu Rong, Cho Kathleen R, Thomas Dafydd G, Gossner Gabrielle, Liu J Rebecca, Giordano Thomas J, Shedden Kerby A, Misek David E, Lubman David M
Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.
Proteomics Clin Appl. 2008 Mar 7;2(4):571-584. doi: 10.1002/prca.200780004.
Ovarian cancer, the second most common gynecological malignancy, accounts for 3% of all cancers among women in the United States, and has a high mortality rate, largely because existing therapies for widespread disease are rarely curative. Ovarian endometrioid adenocarcinoma (OEA) accounts for about 20% of the overall incidence of all ovarian cancer. We have used proteomics profiling to characterize low stage (FIGO stage 1 or 2) versus high stage (FIGO stage 3 or 4) human OEAs. In general, the low stage tumors lacked p53 mutations and had frequent CTNNB1, PTEN, and/or PIK3CA mutations. The high stage tumors had mutant p53, were usually high grade, and lacked mutations predicted to deregulate Wnt/β-catenin and PI3K/Pten/Akt signaling. We utilized 2-D liquid-based separation/mass mapping techniques to elucidate molecular weight and pI measurements of the differentially expressed intact proteins. We generated 2-D protein mass maps to facilitate the analysis of protein expression between both the low stage and high stage tumors. These mass maps (over a pI range of 5.6-4.6) revealed that the low stage OEAs demonstrated protein over-expression at the lower pI ranges (pI 4.8-4.6) in comparison to the high stage tumors, which demonstrated protein over-expression in the higher pI ranges (pI 5.4-5.2). These data suggest that both low and high stage OEAs have characteristic pI signatures of abundant protein expression probably reflecting, at least in part, the different signaling pathway defects that characterize each group. In this study, the low stage OEAs were distinguishable from high stage tumors based upon the proteomic profiles. Interestingly, when only high-grade (grade 2 or 3) OEAs were included in the analysis, the tumors still tended to cluster according to stage, suggesting that the altered protein expression was not solely dependent upon tumor cell differentiation. Further, these protein profiles clearly distinguish OEA from other types of ovarian cancer at the protein level.
卵巢癌是第二常见的妇科恶性肿瘤，在美国女性所有癌症中占3%，且死亡率很高，这主要是因为针对广泛扩散疾病的现有疗法很少能治愈。卵巢子宫内膜样腺癌（OEA）约占所有卵巢癌总发病率的20%。我们利用蛋白质组学分析来表征低分期（国际妇产科联盟（FIGO）1期或2期）与高分期（FIGO 3期或4期）的人类OEA。一般来说，低分期肿瘤缺乏p53突变，而CTNNB1、PTEN和/或PIK3CA突变频繁。高分期肿瘤有p53突变，通常为高级别，且缺乏预计会使Wnt/β-连环蛋白和PI3K/Pten/Akt信号传导失调的突变。我们利用基于二维液相的分离/质谱图谱技术来阐明差异表达的完整蛋白质的分子量和等电点测量值。我们生成了二维蛋白质质谱图，以促进对低分期和高分期肿瘤之间蛋白质表达的分析。这些质谱图（等电点范围为5.6 - 4.6）显示，与高分期肿瘤相比，低分期OEA在较低等电点范围（等电点4.8 - 4.6）表现出蛋白质过表达，而高分期肿瘤在较高等电点范围（等电点5.4 - 5.2）表现出蛋白质过表达。这些数据表明，低分期和高分期OEA都有丰富蛋白质表达的特征性等电点特征，这可能至少部分反映了每组所特有的不同信号通路缺陷。在本研究中，基于蛋白质组学图谱，低分期OEA可与高分期肿瘤区分开来。有趣的是，当分析中仅纳入高级别（2级或3级）OEA时，肿瘤仍倾向于根据分期聚类，这表明蛋白质表达的改变并非仅取决于肿瘤细胞分化。此外，这些蛋白质图谱在蛋白质水平上清楚地将OEA与其他类型的卵巢癌区分开来。
