6月12日,，Cell Research雜志報(bào)道了調(diào)節(jié)乳腺癌骨轉(zhuǎn)移的分泌蛋白的最新研究進(jìn)展。骨轉(zhuǎn)移是乳腺癌的常見并發(fā)癥,，也是其致死,、致殘的重要原因,。在轉(zhuǎn)移過程中，分泌蛋白在癌細(xì)胞與宿主基質(zhì)的相互作用上發(fā)揮重要的作用,。
為了鑒定與乳腺癌轉(zhuǎn)移相關(guān)的分泌蛋白,，研究者利用無標(biāo)記蛋白組分析比較了四種具有不同骨轉(zhuǎn)移能力的來源于人乳腺癌細(xì)胞MDA-MB-231(MDA231) 的細(xì)胞系的蛋白分泌組。在培養(yǎng)過有骨轉(zhuǎn)移能力的癌細(xì)胞的培養(yǎng)基中,，共發(fā)現(xiàn)128種蛋白的水平一致性上調(diào)或下調(diào),。這些發(fā)生水平改變的蛋白的功能包括受體結(jié)合和肽酶抑制。
通過對乳腺癌轉(zhuǎn)錄組的分析,，研究者選取在骨轉(zhuǎn)移癌細(xì)胞中下調(diào)的半胱氨酸蛋白酶抑制劑E/M（CST6）作為進(jìn)一步研究的對象,。其研究結(jié)果顯示，CST6抑制乳腺癌的細(xì)胞增殖,，集落形成,，遷徙和侵襲。腫瘤來源的可溶性CST6介導(dǎo)針對癌細(xì)胞運(yùn)動(dòng)能力的功能抑制,。更重要的是,，在癌細(xì)胞中表達(dá)CST6可顯著緩解實(shí)驗(yàn)小鼠的溶骨性轉(zhuǎn)移和死亡。而CST6下調(diào)明顯增強(qiáng)癌細(xì)胞的骨轉(zhuǎn)移和縮短小鼠壽命,。
總之,，該研究提供了骨趨向性乳腺癌系統(tǒng)的分泌蛋白質(zhì)組分析。它還證實(shí),，分泌性CST6的確是乳腺癌骨轉(zhuǎn)移的抑制因子,。（生物谷bioon.com）
doi:10.1016/j.cell.2011.10.017
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Differential secretome analysis reveals CST6 as a suppressor of breast cancer bone metastasis
Lei Jin1,*, Yan Zhang2,*, Hui Li1, Ling Yao2, Da Fu1, Xuebiao Yao3, Lisa X Xu2, Xiaofang Hu2 and Guohong Hu1
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.
