Effects of Dickkopf-1 (DKK-1) on Prostate Cancer Growth and Bone Metastasis.
Effects of Dickkopf-1 (DKK-1) on Prostate Cancer Growth and Bone Metastasis.
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DOI：
10.3390/cells12232695
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发表时间：
2023-11-24
期刊：
影响因子：
6
通讯作者：
Rosol, Thomas J.
中科院分区：
文献类型：
--
作者：
Yuan, Shiyu;Hoggard, Nathan K.;Kantake, Noriko;Hildreth, Blake E.;Rosol, Thomas J.
成骨细胞骨转移通常在晚期前列腺癌（PCa）患者中检测到，并与死亡率增加相关。Dickkopf-1（DKK-1）拮抗经典的WNT/β-catenin信号传导，并在骨转移中发挥复杂的作用。我们使用成骨犬PCa细胞系Probasco探索癌细胞特异性DKK-1在PCa生长、转移和癌-骨相互作用中的功能。将Probasco或Probasco + DKK-1（用人DKK-1转导的细胞）注射到无胸腺裸鼠的胫骨或左心室中。通过生物发光成像检测体内骨转移，并通过显微计算机断层扫描和组织病理学进行评估。在体外评价癌细胞增殖、迁移、基因/蛋白表达及其对原代鼠成骨细胞和破骨细胞的影响。DKK-1增加了癌症生长并刺激了细胞迁移，而不依赖于经典的WNT信号传导。通过DKK-1增强的癌症进展与增加的细胞增殖、NF-kB/p65信号传导的上调、通过非经典WNT/JNK信号传导的下调来抑制半胱天冬酶依赖性凋亡以及上皮-间充质转化基因的表达增加相关。此外，DKK-1减弱了Probasco细胞的成骨活性，骨转移减少了癌症诱导的髓内编织骨形成。骨形成减少可能是由于骨微环境中OPG/RANKL比值降低抑制成骨细胞分化和刺激破骨细胞活性所致。本研究表明，DKK-1在PCa骨转移中的促癌作用与骨转移生长增加、骨诱导减少和通过经典WNT非依赖性途径改变信号传导相关。DKK-1可能成为前列腺癌治疗的一个新靶点。
Osteoblastic bone metastases are commonly detected in patients with advanced prostate cancer (PCa) and are associated with an increased mortality rate. Dickkopf-1 (DKK-1) antagonizes canonical WNT/β-catenin signaling and plays a complex role in bone metastases. We explored the function of cancer cell-specific DKK-1 in PCa growth, metastasis, and cancer–bone interactions using the osteoblastic canine PCa cell line, Probasco. Probasco or Probasco + DKK-1 (cells transduced with human DKK-1) were injected into the tibia or left cardiac ventricle of athymic nude mice. Bone metastases were detected by bioluminescent imaging in vivo and evaluated by micro-computed tomography and histopathology. Cancer cell proliferation, migration, gene/protein expression, and their impact on primary murine osteoblasts and osteoclasts, were evaluated in vitro. DKK-1 increased cancer growth and stimulated cell migration independent of canonical WNT signaling. Enhanced cancer progression by DKK-1 was associated with increased cell proliferation, up-regulation of NF-kB/p65 signaling, inhibition of caspase-dependent apoptosis by down-regulation of non-canonical WNT/JNK signaling, and increased expression of epithelial-to-mesenchymal transition genes. In addition, DKK-1 attenuated the osteoblastic activity of Probasco cells, and bone metastases had decreased cancer-induced intramedullary woven bone formation. Decreased bone formation might be due to the inhibition of osteoblast differentiation and stimulation of osteoclast activity through a decrease in the OPG/RANKL ratio in the bone microenvironment. The present study indicated that the cancer-promoting role of DKK-1 in PCa bone metastases was associated with increased growth of bone metastases, reduced bone induction, and altered signaling through the canonical WNT-independent pathway. DKK-1 could be a promising therapeutic target for PCa.
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影响因子：
2.8
作者：
Hall, Christopher L.;Daignault, Stephanie D.;Shah, Rajal B.;Pienta, Kenneth J.;Keller, Evan T.
通讯作者：
Keller, Evan T.
影响因子：
4
作者：
Kasoha, Mariz;Bohle, Rainer M.;Solomayer, Erich-Franz
通讯作者：
Solomayer, Erich-Franz
DOI：
10.1007/978-1-61779-415-5_2
发表时间：
2012-01-01
期刊：
BONE RESEARCH PROTOCOLS, SECOND EDITION
影响因子：
--
作者：
Bakker, Astrid D.;Klein-Nulend, Jenneke
通讯作者：
Klein-Nulend, Jenneke
影响因子：
7.5
作者：
Li, Xin;Wang, Jingjing;Liu, Zhiqiang
通讯作者：
Liu, Zhiqiang
影响因子：
7.3
作者：
Chu HY;Chen Z;Wang L;Zhang ZK;Tan X;Liu S;Zhang BT;Lu A;Yu Y;Zhang G
通讯作者：
Zhang G