Clinical validation of candidate genes associated with prostate cancer progression in the CWR22 model system using tissue microarrays.
Clinical validation of candidate genes associated with prostate cancer progression in the CWR22 model system using tissue microarrays.
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发表时间：
2002-03
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影响因子：
11.2
通讯作者：
S. Mousses;L. Bubendorf;U. Wagner;G. Hostetter;J. Kononen;R. Cornelison;N. Goldberger;A. Elkahloun;N. Willi;P. Koivisto;William Ferhle;M. Raffeld;G. Sauter;O. Kallioniemi
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作者：
S. Mousses;L. Bubendorf;U. Wagner;G. Hostetter;J. Kononen;R. Cornelison;N. Goldberger;A. Elkahloun;N. Willi;P. Koivisto;William Ferhle;M. Raffeld;G. Sauter;O. Kallioniemi
为了探索前列腺癌进展的分子机制，我们应用组织微阵列（TMAs）分析CWR 22异种移植模型系统的cDNA微阵列分析发现的候选基因靶点的表达。通过mRNA原位杂交和蛋白质免疫组化对来自疾病进展不同阶段的544个临床标本的TMA进行了探测。有一个很好的相关性（r = 0.96; n = 16）之间的表达水平的基因在异种移植的cDNA微阵列和mRNA原位杂交的TMA。难治性CWR 22 R异种移植物中最高度过表达的基因之一是S100 P基因。该基因编码与衰老丧失有关的钙信号分子，通过TMA分析也与临床肿瘤的进展显著相关（P < 0.001），表明该途径在难治性和转移性前列腺癌中失调。相反，在体内验证了在CWR 22模型系统中肿瘤进展期间下调的两个基因：与原发性肿瘤相比，晶状体蛋白μ（MRM）和LIM结构域蛋白LMO 4在肿瘤难治性肿瘤中均显示出显著较低的mRNA水平（P < 0.001）。这些结果说明了一种策略，在mRNA和蛋白质水平的基因靶发现差异表达的cDNA微阵列实验中的癌症模型系统的快速临床验证。
To explore molecular mechanisms of prostate cancer progression, we applied tissue microarrays (TMAs) to analyze expression of candidate gene targets discovered by cDNA microarray analysis of the CWR22 xenograft model system. A TMA with 544 clinical specimens from different stages of disease progression was probed by mRNA in situ hybridization and protein immunohistochemistry. There was an excellent correlation (r = 0.96; n = 16) between the expression levels of the genes in the xenografts by cDNA microarray and mRNA in situ hybridization on a TMA. One of the most highly overexpressed genes in hormone-refractory CWR22R xenografts was the S100P gene. This gene, coding for a calcium signaling molecule implicated in the loss of senescence, was also significantly associated with progression in clinical tumors by TMA analysis (P < 0.001), suggesting dysregulation of this pathway in hormone-refractory and metastatic prostate cancers. Conversely, two genes that were down-regulated during tumor progression in the CWR22 model system were validated in vivo: crystallin mu (CRYM) and a LIM-domain protein LMO4 both showed significantly lower mRNA levels in hormone-refractory tumors as compared with primary tumors (P < 0.001). These results illustrate a strategy for rapid clinical validation at the mRNA and protein level of gene targets found to be differentially expressed in cDNA microarray experiments of model systems of cancer.