Dickkopf-1 expression increases early in prostate cancer development and decreases during progression from primary tumor to metastasis.
Dickkopf-1 expression increases early in prostate cancer development and decreases during progression from primary tumor to metastasis.
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DOI：
10.1002/pros.20805
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发表时间：
2008-09-15
期刊：
影响因子：
2.8
通讯作者：
Keller, Evan T.
中科院分区：
文献类型：
--
作者：
Hall, Christopher L.;Daignault, Stephanie D.;Shah, Rajal B.;Pienta, Kenneth J.;Keller, Evan T.
前列腺癌（PCa）经常转移到骨，并诱导成骨细胞病变。我们先前通过Wnt抑制剂dickkopf-1（DKK-1）的过表达证明，Wnt有助于体内PCa骨病变的成骨成分。为了检测DKK-1表达在PCa进展过程中的临床意义，通过免疫组织化学对组织微阵列进行DKK-1蛋白染色。发现PIN和原发性病变中的DKK-1表达指数（EI）与非肿瘤组织相比增加（分别为106±10 vs. 19±6，其中EI是表达百分比和染色强度的乘积）。还发现DKK-1表达在所有PCa转移性病变中（56±21 EI）高于非肿瘤组织，但与原发性PCa病变相比显著降低（p<0.008）。DKK-1的下降与β-连环蛋白染色从细胞核向细胞质的转移相关，这表明在PCa进展期间观察到的DKK-1水平下降的可能机制。在转移病灶内，除了淋巴结转移外，相对于所有软组织PCa转移病灶，DKK-1表达在PCa骨转移中最少。DKK-1在PCa转移灶中的高表达与患者总体生存期较短进一步相关。总之，这些数据表明，DKK-1表达升高是PCa的早期事件，并且随着PCa进展，DKK-1表达下降，特别是在晚期骨转移中。骨转移瘤中DKK-1的下降可以揭示Wnt的成骨活性。这些数据支持一个模型，其中DKK-1是一个分子开关，将前列腺癌骨病变的表型从溶骨性转变为成骨性。
Prostate cancer (PCa) frequently metastasizes to the bone and induces osteoblastic lesions. We previously demonstrated through over-expression of the Wnt inhibitor dickkopf-1 (DKK-1) that Wnts contribute to the osteoblastic component of PCa osseous lesions in vivo. To test the clinical significance of DKK-1 expression during PCa progression, tissue microarrays were stained for DKK-1 protein by immunohistochemistry. DKK-1 expression index (EI) was found to increase in PIN and primary lesions compared to non-neoplastic tissue (106±10 vs. 19±6, respectively, where the EI is the product of the percent expression and staining intensity). DKK-1 expression was also found to be higher in all PCa metastatic lesions (56±21 EI) compared to non-neoplastic tissues but was significantly decreased vs. primary PCa lesions (p<0.008). The decline in DKK-1 correlated with a shift of β-catenin staining from the nucleus to the cytoplasm suggesting possible mechanism for the observed decrease in DKK-1 levels during PCa progression. Within metastatic lesions, DKK-1 expression was least abundant in PCa bone metastases relative to all soft tissue PCa metastatic lesions except lymph node metastases. High DKK-1 expression within PCa metastases was further associated with shorter over-all patient survival. Taken together, these data demonstrate that elevated DKK-1 expression is an early event in PCa and that as PCa progresses DKK-1 expression declines, particularly in advanced bone metastases. The decline of DKK-1 in bone metastases can unmask Wnts’ osteoblastic activity. These data support a model in which DKK-1 is a molecular switch that transitions the phenotype of PCa osseous lesions from osteolytic to osteoblastic.
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影响因子：
20.3
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