Clinical-translational approaches to the Nm23-H1 metastasis suppressor.
Clinical-translational approaches to the Nm23-H1 metastasis suppressor.
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DOI：
10.1158/1078-0432.ccr-08-0238
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发表时间：
2008-08-15
期刊：
影响因子：
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通讯作者：
Miller KD
中科院分区：
文献类型：
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作者：
Steeg PS;Horak CE;Miller KD
nm 23-H1是第一个发现的转移抑制基因，能显著降低转移而不影响原发肿瘤的大小。认为至少有三种机制有助于Nm 23-H1的转移抑制作用：（a）其对ATP-柠檬酸裂解酶、醛缩酶C和ras的激酶抑制剂的组氨酸激酶活性，最后使丝裂原活化蛋白激酶信号转导失活;（B）滴定“游离”Nm 23-H1并抑制其抑制转移能力的结合蛋白;和（c）改变Nm 23-H1下游的基因表达，特别是与溶血磷脂酸受体内皮分化基因-28（EDG 2）的反向关联。大多数转移抑制基因，包括Nm 23-H1，影响转移定植，这是肿瘤细胞在远处生长的产物;因此，它们具有高度的翻译价值。一项II期试验正在进行中，以测试一种化合物，高剂量醋酸甲羟孕酮（MPA），作为一种非常规的糖皮质激素，将刺激乳腺癌细胞重新表达Nm 23-H1，并限制随后的转移定植的假设。
Nm23-H1significantly reduces metastasis without effects on primary tumor size and was the first discovered metastasis suppressor gene. At least three mechanisms are thought to contribute to the metastasis-suppressive effect of Nm23-H1: (a) its histidine kinase activity toward ATP-citrate lyase, aldolase C, and the kinase suppressor of ras, with the last inactivating mitogen-activated protein kinase signaling; (b) binding proteins that titer out "free" Nm23-H1 and inhibit its ability to suppress metastasis; and (c) altered gene expression downstream of Nm23-H1, particularly an inverse association with the lysophosphatidic acid receptor endothelial differentiation gene-28 (EDG2). Most metastasis suppressor genes, including Nm23-H1, affect metastatic colonization, which is the outgrowth of tumor cells in distant locations; therefore, they are of high translational interest. A phase II trial is ongoing to test the hypothesis that a compound, high-dose medroxy-progesterone acetate (MPA), used as an unconventional gluocorticoid, will stimulate breast cancer cells to reexpress Nm23-H1and limit subsequent metastatic colonization.