TGF-β的復(fù)雜細(xì)胞信號傳導(dǎo)途徑,，圖片來自維基共享資源,。
信號告訴細(xì)胞表現(xiàn)得像癌細(xì)胞那樣存活，生長和不受控制的增殖,。信號也能夠告訴帶有癌變特征的細(xì)胞停止生長或死亡,。在乳腺癌中，一種狡猾的稱作TGF-β的信號發(fā)揮著兩種作用：有時促進(jìn)腫瘤產(chǎn)生,，有時抑制腫瘤產(chǎn)生,。
來自美國科羅拉多大學(xué)癌癥研究中心的研究人員最近在Oncogene 期刊上發(fā)表一篇論文，詳細(xì)地描述了腫瘤如何能夠調(diào)控TGF-β信號傳導(dǎo)開關(guān),，當(dāng)它促進(jìn)腫瘤產(chǎn)生時則允許醫(yī)生完全阻斷這種途徑,，而當(dāng)它仍然起著抑制腫瘤生長時則讓它保持完整。
科羅拉多大學(xué)癌癥研究中心研究員,、科羅拉多大學(xué)醫(yī)學(xué)院婦產(chǎn)科副教授和該論文的通訊作者Heide Ford說,，“本質(zhì)上講,，腫瘤劫持一種胚胎程序,，并啟動這種程序。”
胚胎生長很快,，因此需要細(xì)胞快速增殖并能夠遷移到胚胎其他區(qū)域,。在人發(fā)育早期，我們依賴一種稱作SIX1的轉(zhuǎn)錄因子產(chǎn)生這種野草般瘋狂生長和靈敏運動,。
然后,，成年時，我們的大多數(shù)細(xì)胞關(guān)閉這種SIX1途徑,，我們不再需要爆炸性生長或運動,，因此這種途徑在我們的基因組中沉睡下來。
大多數(shù)乳腺癌喚醒SIX1,。這篇Oncogene 研究論文仔細(xì)描述了SIX1如何調(diào)控TGF-β信號傳導(dǎo)開關(guān),，切換到抑制或促進(jìn)腫瘤的狀態(tài),。
SIX1產(chǎn)生調(diào)節(jié)基因活性的稱作microRNAs的小分子。在這種情形中,，SIX1產(chǎn)生的microRNAs附著到并減弱TGF-β中阻止細(xì)胞生長的氨基酸序列部分,。當(dāng)TGF-β被沉默時，這種信號并不阻止細(xì)胞生長,，相反促進(jìn)這些細(xì)胞遷移到新的組織,。表達(dá)SIX1和與它相關(guān)聯(lián)的microRNAs就像是移除魯莽青少年駕駛的福特野馬敞篷車(Mustang convertible)的限速器。
Ford說,，“高水平的SIX1或與SIX1相關(guān)聯(lián)的microRNAs是乳腺癌正在利用TGF-β信號傳導(dǎo)促進(jìn)腫瘤生長的征兆,。”病人患上的乳腺癌若擁有高水平的SIX1或與SIX1相關(guān)聯(lián)的microRNAs，那么腫瘤患者可能得益于“TGF-β抑制劑”,，因為這種藥物能夠關(guān)閉這種信號,，而且當(dāng)前正在進(jìn)行臨床試驗。相反,，擁有低水平SIX1的乳腺癌患者最好保持TGF-β信號傳導(dǎo)完整,，在這種情形中，這種信號有可能幫助這些乳腺癌患者對抗她們的腫瘤,。
在未來,，F(xiàn)ord希望直接靶向SIX1。
她說,，“因為在大多數(shù)成熟組織中我們不需要SIX1,，如果我們能夠靶向SIX1，我們就可能能夠在多個戰(zhàn)場抑制腫瘤生長同時很少有副作用,。”
如今因發(fā)現(xiàn)靶標(biāo)SIX,，F(xiàn)ord和她的同事們正開發(fā)新藥物阻止這種促進(jìn)腫瘤生長的因子發(fā)揮作用。(生物谷：towersimper編譯)
doi10.1038/onc.2012.11
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The miR-106b-25 cluster targets Smad7, activates TGF-β signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer
A L Smith, R Iwanaga, D J Drasin, D S Micalizzi, R L Vartuli, A-C Tan and H L Ford
The role of TGF-β signaling in tumorigenesis is paradoxical: it can be tumor suppressive or tumor promotional, depending on context. The metastatic regulator, Six1, was recently shown to mediate this switch, providing a novel means to explain this elusive ‘TGF-β paradox’. Herein, we identify a mechanism by which Six1 activates the tumor promotional arm of TGF-β signaling, via its ability to upregulate the miR-106b-25 microRNA cluster, and further identify a novel function for this cluster of microRNAs. Although expression of the miR-106b-25 cluster is known to overcome TGF-β-mediated growth suppression via targeting p21 and BIM, we demonstrate for the first time that this same cluster can additionally target the inhibitory Smad7 protein, resulting in increased levels of the TGF-β type I receptor and downstream activation of TGF-β signaling. We further show that the miR-106b-25 cluster is sufficient to induce an epithelial-to-mesenchymal transition and a tumor initiating cell phenotype, and that it is required downstream of Six1 to induce these phenotypes. Finally, we demonstrate a significant correlation between miR-106b, Six1, and activated TGF-β signaling in human breast cancers, and further show that high levels of miR-106b and miR-93 in breast tumors significantly predicts shortened time to relapse. These findings expand the spectrum of oncogenic functions of miR-106b-25, and may provide a novel molecular explanation, through the Six1 regulated miR-106b-25 cluster, by which TGF-β signaling shifts from tumor suppressive to tumor promoting.
