Breast cancer-derived Dickkopf1 inhibits osteoblast differentiation and osteoprotegerin expression: implication for breast cancer osteolytic bone metastases.
Breast cancer-derived Dickkopf1 inhibits osteoblast differentiation and osteoprotegerin expression: implication for breast cancer osteolytic bone metastases.
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DOI：
10.1002/ijc.23625
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发表时间：
2008-09-01
影响因子：
6.4
通讯作者：
Li, Yonghe
中科院分区：
文献类型：
--
作者：
Bu, Guojun;Lu, Wenyan;Liu, Chia-Chen;Selander, Katri;Yoneda, Toshiyuki;Hall, Christopher;Keller, Evan T.;Li, Yonghe
大多数乳腺癌骨转移形成溶骨性病变，但肿瘤引起骨吸收和破坏的机制尚不完全清楚。虽然Wnt/β-catenin信号通路在乳腺癌的发生发展中具有重要作用，但该信号通路在乳腺癌骨转移中的作用尚不清楚。Dickkopf1(DKK1)是一种分泌型Wnt/β-catenin拮抗剂。在本研究中，我们证明了Wnt/β-catenin信号的激活增强了乳腺癌细胞中DKK1的表达，并且DKK1的过度表达在乳腺癌中是一种常见的事件。我们还发现，优先形成溶骨性骨转移的人乳腺癌细胞株表现出WNT/β-连环蛋白信号和DKK1表达水平的增加。此外，我们还发现，乳腺癌细胞产生的Dkk1阻断了Wnt3a诱导的成骨细胞前体C2C12细胞的成骨分化和骨保护素(OPG)的表达，并且这些作用可以被特异性的抗Dkk1抗体所中和。此外，我们还发现乳腺癌细胞条件培养液能够阻断Wnt3a诱导的C2C12细胞中NF-kappaB配体的减少。最后，我们证明，通过RNAi沉默Dkk1表达的乳腺癌细胞的条件培养液无法阻止Wnt3a诱导的C2C12成骨细胞分化和OPG表达。综上所述，这些结果表明，乳腺癌产生的Dkk1可能是原发性乳腺肿瘤和继发性溶骨性骨转移之间的重要机制联系。
Most breast cancer metastases in bone form osteolytic lesions, but the mechanisms of tumor-induced bone resorption and destruction are not fully understood. Although it is well recognized that Wnt/β-catenin signaling is important for breast cancer tumorigenesis, the role of this pathway in breast cancer bone metastasis is unclear. Dickkopf1 (Dkk1) is a secreted Wnt/β-catenin antagonist. In the present study, we demonstrated that activation of Wnt/β-catenin signaling enhanced Dkk1 expression in breast cancer cells and that Dkk1 over-expression is a frequent event in breast cancer. We also found that human breast cancer cell lines that preferentially form osteolytic bone metastases exhibited increased levels of Wnt/β-catenin signaling and Dkk1 expression. Moreover, we showed that breast cancer cell-produced Dkk1 blocked Wnt3A-induced osteoblastic differentiation and osteoprotegerin (OPG) expression of osteoblast precursor C2C12 cells, and that these effects could be neutralized by a specific anti-Dkk1 antibody. In addition, we found that breast cancer cell conditioned media were able to blocked Wnt3A-induced NF-kappaB ligand reduction in C2C12 Cells. Finally, we demonstrated that conditioned media from breast cancer cells in which Dkk1 expression had been silenced via RNAi were unable to block Wnt3A-induced C2C12 osteoblastic differentiation and OPG expression. Taken together, these results suggest that breast cancer-produced Dkk1 may be an important mechanistic link between primary breast tumors and secondary osteolytic bone metastases.
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影响因子：
6.2
作者：
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