基質金屬蛋白酶(MMP)是水解細胞外基質的蛋白裂解酶,。MMPs幾乎能降解ECM中的各種蛋白成分,破壞腫瘤細胞侵襲的組織學屏障,，在腫瘤侵襲轉移中起關鍵性作用，從而在腫瘤浸潤轉移中的作用日益受到重視,，被認為是該過程中主要的蛋白水解酶,。
基質金屬蛋白酶1(MMP1)，是一種膠原蛋白酶及G蛋白偶聯(lián)的蛋白酶激活受體1(PAR1)的激活因子,，是近年來新發(fā)現(xiàn)的一個與腫瘤形成及遷移有關的靶點,。然而在老鼠癌癥模型，MMP1的功能同源物還不明確,。
近日,，來自美國塔芙茨醫(yī)學中心的研究人員Athan Kuliopulos等人發(fā)現(xiàn)，基質金屬蛋白酶1a（Mmp1a）是老鼠的MMP1功能同源物,，能夠促進肺癌及黑色素瘤的發(fā)生及轉移,。相關論文發(fā)表在5月9日的The Journal of Biological Chemistry。
研究發(fā)現(xiàn),，Lewis肺癌(LLC1)以及老鼠原發(fā)性黑色素瘤細胞含有激活的BRAF,，能夠高水平的表達內(nèi)源性Mmp1a。
在三維培養(yǎng)基質,，沉默Mmp1a或PAR1后會抑制肺癌細胞的侵襲性生長。相反的,，在沒有表達內(nèi)源性Mmp1a的上皮細胞,，Mmp1a的異位表達會使上皮細胞表現(xiàn)出侵襲表型。
與Mmp1a作為PAR1的激活因子一致,，抑制或者是沉默PAR1會失去Mmp1a介導的侵襲表型,。
在腫瘤的異種移植模型,，敲除Mmp1a后，腫瘤的生成,、入侵及轉移發(fā)生顯著減少,。
總的來說，該研究表明,，癌細胞衍生的Mmp1a作為MMP1的一個功能同源物,，賦予了細胞的致癌及轉移能力。（生物谷Deepblue編譯）
doi: 10.1074/jbc.M112.356303
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Matrix metalloprotease-1a promotes tumorigenesis and metastasis
Caitlin J. Foley, Chi Luo, Katie O'Callaghan, Philip W. Hinds, Lidija Covic and Athan Kuliopulos.
Matrix metalloprotease-1 (MMP1), a collagenase and activator of the G protein-coupled protease activated receptor-1 (PAR1), is an emerging new target implicated in oncogenesis and metastasis in diverse cancers.However, the functional mouse homologue of MMP1 in cancer models has not yet been clearly defined. We report here that Mmp1a is a functional MMP1 homologue that promotes invasion and metastatic progression of mouse lung cancer and melanoma.Lewis lung carcinoma (LLC1), and primary mouse melanoma cells harboring active BRAF, express high levels of endogenous Mmp1a which is required for invasion through collagen.Silencing of either Mmp1a or PAR1 suppressed invasive stellate growth of lung cancer cells in 3-dimensional matrices. Conversely, ectopic expression of Mmp1a conferred an invasive phenotype in epithelial cells that do not express endogenous Mmp1a.Consistent with Mmp1a acting as a PAR1 agonist in an autocrine loop, inhibition or silencing of PAR1 resulted in a loss of the Mmp1a-driven invasive phenotype.Knockdown of Mmp1a on tumor cells resulted in significantly decreased tumorigenesis, invasion, and metastasis in xenograft models. Together, these data demonstrate that cancer cell-derived Mmp1a acts as a robust functional homologue of MMP1 by conferring pro-tumorigenic and metastatic behavior to cells.
