3月3日，国际著名学术期刊《The Journal of Clinical Investigation》在线发表了健康科学研究所胡国宏研究组与山东大学齐鲁医院杨其峰研究组合作完成的题为“DLC1-dependent parathyroid hormone - like hormone inhibition suppresses breast cancer bone metastasis”的最新研究成果。论文首次报道了DLC1（deleted in liver cancer 1）通过抑制SMAD3 连接区域的磷酸化，降低TGFβ诱导的PTHLH表达水平，最终阻碍乳腺癌的骨转移进程。

　　乳腺癌是对女性健康构成很大威胁的一种恶性疾病。而乳腺癌向重要器官如骨、肺、脑、肝等的转移是乳腺癌致死的主要原因。临床上的数据显示大约70%的晚期乳腺癌病人会发生骨转移。乳腺癌发生骨转移可能会给病人带来疼痛、骨折和高钙血等症状，这使得病人生活质量非常之低。以前的研究表明在乳腺癌骨转移过程中破骨细胞发挥着关键性的作用，临床上用于治疗乳腺癌骨转移的两类药物Bisphosphonates和RANKL抗体（比如Denosumab）主要机制即是抑制破骨细胞活性，具体而言，前者能引发破骨细胞发生细胞凋亡，后者通过竞争性结合RANKL而阻碍破骨细胞的成熟。两种药物能在一定程度上缓解病人的症状但对患者的生存率影响不大，因此开发出更有效的阻止乳腺癌骨转移的药物迫在眉睫。

　　健康科学研究所博士研究生王宇峰等在胡国宏研究员的指导下，与齐鲁医院合作，利用具有不同骨转移能力的乳腺癌细胞亚系作为模型，结合小动物活体成像的检测发现DLC1在乳腺癌骨转移过程中起着关键性的负调控作用。他们的研究证明，DLC1功能的行使依赖于它失活RHO-ROCK通路，继而抑制TGFβ诱导的SMAD3 linker region磷酸化。DLC1对后者的抑制降低了TGFβ诱导的PTHLH的转录和分泌，从而减少骨转移微环境中的成熟破骨细胞，最终阻碍了乳腺癌的破骨性转移。同时他们用一种已通过FDA审批的ROCK抑制剂Fasudil治疗乳腺癌骨转移，结果显示Fasudil能有效阻遏骨转移的进程，这暗示这种药物或许具有进行临床试验的价值。该研究首次证明DLC1-RHO信号通路在调控乳腺癌骨转移微环境中的重要作用，也为临床上治疗乳腺癌骨转移提供了新思路。

　　该项工作获得国家科技部973项目、国家自然科学基金委及中国科学院项目的经费资助。

　　DLC1 inhibits bone metastasis by blocking TGFβ-induced PTHLH production

　　Breast cancer is one of the major causes of cancer-related deaths worldwide, mainly due to outgrowth of cancer cells in vital organs including the bone, lungs, liver and brain. The majority of patients with advanced breast cancer will develop bone metastases and suffer from severe pains and eventually deaths. Current treatments for bone metastasis have limited efficacy and, therefore, there is an urgent need to identify functional molecules in cancer cell bone colonization as new therapeutic targets.

　　Recently, the research group at Dr.Guohong Hu’s laboratory from the Institute of Health Sciences defined a novel actor to regulate breast cancer bone metastasis. This actor, deleted in liver cancer 1 (DLC1), is an important regulator of TGFβ response. DLC1 suppresses bone metastasis by inactivating Rho GTPases, while Rho-ROCK signaling mediates SMAD3 linker region phosphorylation and TGFβ-induced expression of parathyroid hormone-like hormone (PTHLH), leading to osteoclast maturation for osteolytic colonization. Pharmacological inhibition of Rho-ROCK effectively reduces PTHLH production and breast cancer bone metastasis. These findings define a stroma-dependent paradigm of Rho signaling in cancer bone metastasis and support the application of Rho-ROCK inhibitors as therapy against breast cancer bone metastasis.

　　This study entitled “DLC1-dependent parathyroid hormone–like hormone inhibition suppresses breast cancer bone metastasis” was published online in The Journal of Clinical Investigation on Mar 3, 2014. This work was funded by the Ministry of Science and Technology of China, National Natural Science Foundation of China and Chinese Academy of Sciences.