Deregulation of a Hox protein regulatory network spanning prostate cancer initiation and progression.
Deregulation of a Hox protein regulatory network spanning prostate cancer initiation and progression.
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DOI：
10.1158/1078-0432.ccr-12-0373
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发表时间：
2012-08-15
期刊：
影响因子：
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通讯作者：
Vander Griend DJ
中科院分区：
文献类型：
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作者：
Chen JL;Li J;Kiriluk KJ;Rosen AM;Paner GP;Antic T;Lussier YA;Vander Griend DJ
前列腺癌发育途径的异常活动可能为预测肿瘤的发生和进展以及确定新的治疗靶点提供重要的见解。为此，尽管与前列腺有相同的雄激素依赖性和功能相似性，精囊癌是非常罕见的。我们进行了基因组通路分析，比较了患者匹配的正常前列腺和精囊上皮细胞，以确定肿瘤发生和发展的新途径。使用蛋白质-蛋白质网络算法将衍生的基因表达谱分组为癌症生物模块，以分析它们与已知癌基因的关系。每个合成的生物模块根据公开的前列腺癌患者基因阵列数据集检测其预后能力。分析表明，包含4个同源盒基因家族成员（Meis1、Meis2、Pbx1和HoxA9）的胚胎发育生物模块检测出一组观察等待患者的生存差异（n = 172, P = 0.05），识别出前列腺切除术后更容易复发的生化男性（n = 78, P = 0.02），与Gleason评分相关（r = 0.98, P = 0.02），并区分正常前列腺、原发肿瘤和转移性疾病。与其他类型的癌症相比，Meis1、Meis2和Pbx1在预后不良的肿瘤中表达降低，提示它们在前列腺癌中起抑癌基因的作用。免疫组化染色显示核基底上皮和间质Meis2染色，前列腺肿瘤中Meis2表达缺失。这些数据表明，Hox蛋白辅助因子Meis1、Meis2和Pbx1在抑制前列腺癌的发生和发展中发挥着关键作用。
The aberrant activity of developmental pathways in prostate cancer may provide significant insight into predicting tumor initiation and progression, as well as identifying novel therapeutic targets. To this end, despite shared androgen-dependence and functional similarities to the prostate gland, seminal vesicle cancer is exceptionally rare. We conducted genomic pathway analyses comparing patient-matched normal prostate and seminal vesicle epithelial cells to identify novel pathways for tumor initiation and progression. Derived gene expression profiles were grouped into cancer biomodules using a protein–protein network algorithm to analyze their relationship to known oncogenes. Each resultant biomodule was assayed for its prognostic ability against publically available prostate cancer patient gene array datasets. Analyses show that the embryonic developmental biomodule containing four homeobox gene family members (Meis1, Meis2, Pbx1, and HoxA9) detects a survival difference in a set of watchful-waiting patients (n = 172, P = 0.05), identify men who are more likely to recur biochemically postprostatectomy (n = 78, P = 0.02), correlate with Gleason score (r = 0.98, P = 0.02), and distinguish between normal prostate, primary tumor, and metastatic disease. In contrast to other cancer types, Meis1, Meis2, and Pbx1 expression is decreased in poor-prognosis tumors, implying that they function as tumor suppressor genes for prostate cancer. Immunohistochemical staining documents nuclear basal-epithelial and stromal Meis2 staining, with loss of Meis2 expression in prostate tumors. These data implicate deregulation of the Hox protein cofactors Meis1, Meis2, and Pbx1 as serving a critical function to suppress prostate cancer initiation and progression.