在乳腺癌中,，CCN6是一種細(xì)胞外基質(zhì)蛋白，在疾病早期其表達(dá)是下降的,，因此認(rèn)為CCN6能發(fā)揮腫瘤抑制功能,。然而，無論其作用還是在乳腺癌轉(zhuǎn)移中作用機(jī)制都是未知的,。
骨形態(tài)發(fā)生蛋白（BMPs）構(gòu)成TGF-β超家族的配體,，是誘導(dǎo)上皮間質(zhì)轉(zhuǎn)化（EMT）、細(xì)胞的侵襲和轉(zhuǎn)移的多功能細(xì)胞因子,。在這項(xiàng)最新研究中,，科研人員確定CCN6-BMP4-TAK1蛋白激酶信號通路控制p38 MAP激酶，調(diào)節(jié)腺泡形態(tài)和乳腺癌細(xì)胞的侵襲能力,。
shRNA降低CCN6表達(dá)導(dǎo)致BMP4的上調(diào),，CCN6衰減也誘發(fā)BMP4介導(dǎo)的不依賴于Smad蛋白的TAK1蛋白和p38激酶的激活。相反,，在乳腺癌細(xì)胞中異位表達(dá)CCN6拮抗BMP4介導(dǎo)的TAK1/p38激活,，都通過結(jié)合BMP4蛋白質(zhì)，降低侵襲能力以及BMP4蛋白質(zhì)水平,。
在體內(nèi),，BMP4和p38的降低被證實(shí)與轉(zhuǎn)移相關(guān)。在臨床標(biāo)本中,，研究人員發(fā)現(xiàn)CCN6表達(dá)與BMP4和p38磷酸化的水平呈負(fù)相關(guān),。因此研究數(shù)據(jù)證實(shí)CCN6調(diào)控乳腺癌細(xì)胞的侵襲和轉(zhuǎn)移。（生物谷：Bioon.com）
doi:10.1158/0008-5472.CAN-12-0154
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CCN6 modulates BMP signaling via the Smad-independent TAK1/p38 pathway, acting to suppress metastasis of breast cancer
Anupama Pal1, Wei Huang1, Xin Li1, Kathy A. Toy1, Zaneta Nicolovska-Coleska1, and Celina G Kleer1,*
CCN6 is an extracellular matrix protein that exerts tumor suppressive functions in breast cancer, where its decreased expression is a feature of advanced disease. However, neither its role nor mechanism of action in breast cancer metastasis has been established. Bone morphogenetic proteins (BMPs), which constitute ligands of the TGF-β superfamily, are multifunctional cytokines that induce epithelial-mesenchymal transition (EMT), cell invasion and metastasis. In this study, we identify a CCN6-BMP4-TAK1 kinase signaling pathway that controls the ability of the p38 MAP kinase to regulate acinar morphogenesis and invasion of breast cells. ShRNA-mediated attenuation of CCN6 in human mammary epithelial (HME) cells led to BMP4 upregulation as a major response to exposure to the TGF-β superfamily. CCN6 attenuation also induced BMP4-mediated activation of the Smad-independent TAK1 and p38 kinases. Conversely, ectopic expression of CCN6 in breast cancer cells antagonized BMP4-mediated TAK1/p38 activation and invasive capacity, both by binding BMP4 protein as well as decreasing BMP4 protein levels. Effects on BMP4 and p38 were confirmed in vivo where they correlated with decreased metastasis. In clinical specimens, we found that CCN6 expression was inversely associated with BMP4 and phospho-p38 levels in 69% of invasive breast carcinomas examined, consistent with the functional results. Together our findings identify a novel modifier pathway through which CCN6 acts to limit breast cancer invasion and metastasis.
