Differential secretome analysis reveals CST6 as a suppressor of breast cancer bone metastasis
Differential secretome analysis reveals CST6 as a suppressor of breast cancer bone metastasis
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差异分泌组分析揭示 CST6 是乳腺癌骨转移的抑制剂
DOI：
10.1038/cr.2012.90
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发表时间：
2012-09-01
期刊：
影响因子：
44.1
通讯作者：
Hu, Guohong
中科院分区：
文献类型：
--
作者：
Jin, Lei;Zhang, Yan;Hu, Guohong
骨转移是乳腺癌的常见并发症，也是乳腺癌发病率和死亡率的常见原因。在转移过程中，分泌的蛋白在癌细胞与宿主基质之间的相互作用中起着至关重要的作用。为了表征与乳腺癌骨转移相关的分泌蛋白，我们进行了无标记蛋白质组学分析，比较了四种具有不同骨转移能力的MDA-MB-231 （MDA231）衍生细胞系的分泌组。共发现128种蛋白在嗜骨癌细胞的条件培养基中持续上调/下调。改变后的蛋白具有丰富的分子功能，包括受体结合和肽酶抑制。通过对乳腺癌细胞的转录组学分析，我们选择了半胱抑素E/M (CST6)，一种在骨转移细胞中下调的半胱氨酸蛋白酶抑制剂，用于进一步的功能研究。我们的研究结果表明，CST6抑制乳腺癌细胞的增殖、集落形成、迁移和侵袭。癌细胞来源的可溶性CST6具有抑制癌细胞运动的功能。更重要的是，在动物实验中，癌细胞中CST6的异位表达使小鼠免于明显的溶骨转移和死亡，而CST6敲低可显著增强癌细胞骨转移，缩短动物生存期。总的来说，我们的研究提供了乳腺癌骨向性的系统分泌组分析，并确定分泌的CST6是乳腺癌溶骨转移的真正抑制因子。
Bone metastasis is a frequent complication of breast cancer and a common cause of morbidity and mortality from the disease. During metastasis secreted proteins play crucial roles in the interactions between cancer cells and host stroma. To characterize the secreted proteins that are associated with breast cancer bone metastasis, we preformed a label-free proteomic analysis to compare the secretomes of four MDA-MB-231 (MDA231) derivative cell lines with varied capacities of bone metastasis. A total of 128 proteins were found to be consistently up-/down-regulated in the conditioned medium of bone-tropic cancer cells. The enriched molecular functions of the altered proteins included receptor binding and peptidase inhibition. Through additional transcriptomic analyses of breast cancer cells, we selected cystatin E/M (CST6), a cysteine protease inhibitor down-regulated in bone-metastatic cells, for further functional studies. Our results showed that CST6 suppressed the proliferation, colony formation, migration and invasion of breast cancer cells. The suppressive function against cancer cell motility was carried out by cancer cell-derived soluble CST6. More importantly, ectopic expression of CST6 in cancer cells rescued mice from overt osteolytic metastasis and deaths in the animal study, while CST6 knockdown markedly enhanced cancer cell bone metastasis and shortened animal survival. Overall, our study provided a systemic secretome analysis of breast cancer bone tropism and established secreted CST6 as a bona fide suppressor of breast cancer osteolytic metastasis.