Dangi-Garimella Surabhi, Yun Jieun, Eves Eva M, Newman Martin, Erkeland Stefan J, Hammond Scott M, Minn Andy J, Rosner Marsha Rich
Ben May Department for Cancer Research, Gordon Center for Integrative Sciences, University of Chicago, IL 60637, USA.
EMBO J. 2009 Feb 18;28(4):347-58. doi: 10.1038/emboj.2008.294. Epub 2009 Jan 15.
Raf kinase inhibitory protein (RKIP) negatively regulates the MAP kinase (MAPK), G protein-coupled receptor kinase-2, and NF-kappaB signalling cascades. RKIP has been implicated as a metastasis suppressor for prostate cancer, but the mechanism is not known. Here, we show that RKIP inhibits invasion by metastatic breast cancer cells and represses breast tumour cell intravasation and bone metastasis in an orthotopic murine model. The mechanism involves inhibition of MAPK, leading to decreased transcription of LIN28 by Myc. Suppression of LIN28 enables enhanced let-7 processing in breast cancer cells. Elevated let-7 expression inhibits HMGA2, a chromatin remodelling protein that activates pro-invasive and pro-metastatic genes, including Snail. LIN28 depletion and let-7 expression suppress bone metastasis, and LIN28 restores bone metastasis in mice bearing RKIP-expressing breast tumour cells. These results indicate that RKIP suppresses invasion and metastasis in part through a signalling cascade involving MAPK, Myc, LIN28, let-7, and downstream let-7 targets. RKIP regulation of two pluripotent stem cell genes, Myc and LIN28, highlights the importance of RKIP as a key metastasis suppressor and potential therapeutic agent.
Raf激酶抑制蛋白（RKIP）对丝裂原活化蛋白激酶（MAPK）、G蛋白偶联受体激酶-2和核因子κB信号级联反应起负向调节作用。RKIP被认为是前列腺癌的转移抑制因子，但其机制尚不清楚。在此，我们表明RKIP抑制转移性乳腺癌细胞的侵袭，并在原位小鼠模型中抑制乳腺肿瘤细胞的血管内渗和骨转移。其机制涉及对MAPK的抑制，导致Myc对LIN28转录的减少。LIN28的抑制使乳腺癌细胞中let-7的加工增强。let-7表达升高抑制HMGA2，HMGA2是一种染色质重塑蛋白，可激活包括Snail在内的促侵袭和促转移基因。LIN28的缺失和let-7的表达抑制骨转移，而LIN28可恢复携带表达RKIP的乳腺肿瘤细胞的小鼠的骨转移。这些结果表明，RKIP部分通过涉及MAPK、Myc、LIN28、let-7及其下游let-7靶标的信号级联反应来抑制侵袭和转移。RKIP对两个多能干细胞基因Myc和LIN28的调节，凸显了RKIP作为关键转移抑制因子和潜在治疗剂的重要性。
