DLC1-dependent parathyroid hormone-like hormone inhibition suppresses breast cancer bone metastasis
DLC1-dependent parathyroid hormone-like hormone inhibition suppresses breast cancer bone metastasis
复制标题
DLC1依赖性甲状旁腺激素样激素抑制抑制乳腺癌骨转移
DOI：
10.1172/jci71812
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发表时间：
2014-04-01
影响因子：
15.9
通讯作者：
Hu, Guohong
中科院分区：
文献类型：
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作者：
Wang, Yufeng;Lei, Rong;Hu, Guohong
骨转移是乳腺癌的常见并发症，通常由TGF-β信号加速;然而，关于TGF-β通路在骨转移期间如何调节知之甚少。在这里，我们报告，在肝癌1（DLC 1）缺失是一个重要的调节TGF-β反应和溶骨性转移的乳腺癌细胞。在小鼠模型中，缺乏DLC 1表达的乳腺癌细胞表现出增强的骨转移能力。DLC 1在癌细胞中的敲低促进骨转移，导致小鼠明显的骨质溶解和加速死亡，而DLC 1过表达抑制骨转移。在DLC 1介导的SMAD 3连接区磷酸化和TGF-β诱导的甲状旁腺激素样激素（PTHLH）表达缺失的情况下，Rho-ROCK信号传导的激活，导致破骨细胞成熟以进行溶骨性定植。此外，Rho-ROCK的药理学抑制在体外和体内有效地减少PTHLH产生和乳腺癌骨转移。对临床乳腺肿瘤样本的评估显示，DLC 1表达降低与PTHLH表达升高和器官特异性骨转移有关。总的来说，我们的研究结果定义了癌症中Rho信号传导的基质依赖性范例，并涉及溶骨性骨转移中的Rho-TGF-β串扰。
Bone metastasis is a frequent complication of breast cancer that is often accelerated by TGF-beta signaling; however, little is known about how the TGF-beta pathway is regulated during bone metastasis. Here we report that deleted in liver cancer 1 (DLC1) is an important regulator of TGF-beta responses and osteolytic metastasis of breast cancer cells. In murine models, breast cancer cells lacking DLC1 expression exhibited enhanced capabilities of bone metastasis. Knockdown of DLC1 in cancer cells promoted bone metastasis, leading to manifested osteolysis and accelerated death in mice, while DLC1 overexpression suppressed bone metastasis. Activation of Rho-ROCK signaling in the absence of DLC1 mediated SMAD3 linker region phosphorylation and TGF-beta-induced expression of parathyroid hormone-like hormone (PTHLH), leading to osteoclast maturation for osteolytic colonization. Furthermore, pharmacological inhibition of Rho-ROCK effectively reduced PTHLH production and breast cancer bone metastasis in vitro and in vivo. Evaluation of clinical breast tumor samples revealed that reduced DLC1 expression was linked to elevated PTHLH expression and organ-specific metastasis to bone. Overall, our findings define a stroma-dependent paradigm of Rho signaling in cancer and implicate Rho-TGF-beta crosstalk in osteolytic bone metastasis.