Melatonin suppresses TPA-induced metastasis by downregulating matrix metalloproteinase-9 expression through JNK/SP-1 signaling in nasopharyngeal carcinoma
Melatonin suppresses TPA-induced metastasis by downregulating matrix metalloproteinase-9 expression through JNK/SP-1 signaling in nasopharyngeal carcinoma
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DOI：
10.1111/jpi.12365
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发表时间：
2016-11-01
影响因子：
10.3
通讯作者：
Yang, Shun-Fa
中科院分区：
文献类型：
--
作者：
Ho, Hsin-Yu;Lin, Chiao-Wen;Yang, Shun-Fa
鼻咽癌是东南亚人群中的常见病，具有较高的淋巴转移能力。褪黑素是一种存在于动物、植物、真菌和细菌中的内源性物质，通过几种机制具有抑癌活性。褪黑素介导的肿瘤抑制作用的分子机制尚未完全确定。在这里，我们表明，褪黑素治疗抑制TPA诱导的鼻咽癌细胞运动通过调节基质金属蛋白酶-9(MMP9)的表达。我们还确定了褪黑素抑制基质金属蛋白酶-9表达的信号级联，这涉及到褪黑素调节转录因子特异性蛋白-1(SP-1)-DNA的结合活性。我们的机制分析进一步表明，c-jun氨基末端激酶/丝裂原活化蛋白激酶途径参与了褪黑素介导的肿瘤抑制活性。此外，这些发现表明褪黑素介导的基质金属蛋白酶-9调节和肿瘤抑制能力之间存在功能联系，并为褪黑素诱导的分子和表观遗传调节肿瘤生长的作用提供了新的见解。因此，我们认为褪黑素通过抑制SP-1与DNA的结合来调节TPA诱导的基质金属蛋白酶-9基因的表达，从而抑制鼻咽癌的运动能力。这些结果提供了褪黑素介导的SP-1调节和褪黑素抗鼻咽癌转移作用之间的功能联系。
Nasopharyngeal carcinoma (NPC), a disease common in the South-East Asian population, has high lymph node metastatic ability. Melatonin, an endogenously produced substance present in animals, plants, fungi, and bacteria, has oncostatic activity via several mechanisms. The molecular mechanisms involved in melatonin-mediated tumor inhibitory potential are not completely defined. Here, we show that melatonin treatment inhibits TPA-induced cell motility by regulating the matrix metalloproteinase-9 (MMP-9) expression in NPC. We also identified the signaling cascade through which melatonin inhibits MMP-9 expression; this involves melatonin regulating the binding activity of the transcription factor specificity protein-1 (SP-1)-DNA. Our mechanistic analysis further reveals that the c-Jun N-terminal kinase/mitogen-activated protein kinase pathway is involved in the melatonin-mediated tumor suppressor activity. Furthermore, the findings indicate a functional link between melatonin-mediated MMP-9 regulation and tumor suppressing ability and provide new insights into the role of melatonin-induced molecular and epigenetic regulation of tumor growth. Thus, we conclude that melatonin suppresses the motility of NPC by regulating TPA-induced MMP-9 gene expression via inhibiting SP-1-DNA binding ability. The results provide a functional link between melatonin-mediated SP-1 regulation and the antimetastatic actions of melatonin on nasopharyngeal carcinoma.