JBC：基质金属蛋白酶1a（MMP1）促进肿瘤发生及转移

基质金属蛋白酶(MMP)是水解细胞外基质的蛋白裂解酶。MMPs几乎能降解ECM中的各种蛋白成分,破坏肿瘤细胞侵袭的组织学屏障，在肿瘤侵袭转移中起关键性作用，从而在肿瘤浸润转移中的作用日益受到重视，被认为是该过程中主要的蛋白水解酶。

基质金属蛋白酶1(MMP1)，是一种胶原蛋白酶及G蛋白偶联的蛋白酶激活受体1(PAR1)的激活因子，是近年来新发现的一个与肿瘤形成及迁移有关的靶点。然而在老鼠癌症模型，MMP1的功能同源物还不明确。

近日，来自美国塔芙茨医学中心的研究人员Athan Kuliopulos等人发现，基质金属蛋白酶1a（Mmp1a）是老鼠的MMP1功能同源物，能够促进肺癌及黑色素瘤的发生及转移。相关论文发表在5月9日的The Journal of Biological Chemistry。

研究发现，Lewis肺癌(LLC1)以及老鼠原发性黑色素瘤细胞含有激活的BRAF，能够高水平的表达内源性Mmp1a。

在三维培养基质，沉默Mmp1a或PAR1后会抑制肺癌细胞的侵袭性生长。相反的，在没有表达内源性Mmp1a的上皮细胞，Mmp1a的异位表达会使上皮细胞表现出侵袭表型。

与Mmp1a作为PAR1的激活因子一致，抑制或者是沉默PAR1会失去Mmp1a介导的侵袭表型。

在肿瘤的异种移植模型，敲除Mmp1a后，肿瘤的生成、入侵及转移发生显著减少。

总的来说，该研究表明，癌细胞衍生的Mmp1a作为MMP1的一个功能同源物，赋予了细胞的致癌及转移能力。

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.