Inhibition of matrix metalloproteinase-9 and nuclear factor kappa B contribute to melatonin prevention of motility and invasiveness in HepG2 liver cancer cells
Inhibition of matrix metalloproteinase-9 and nuclear factor kappa B contribute to melatonin prevention of motility and invasiveness in HepG2 liver cancer cells
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DOI：
10.1111/jpi.12092
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发表时间：
2014-01-01
影响因子：
10.3
通讯作者：
Mauriz, Jose L.
中科院分区：
文献类型：
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作者：
Ordonez, Raquel;Carbajo-Pescador, Sara;Mauriz, Jose L.
肝细胞癌（HCC）是世界范围内最致命的人类癌症之一，因为它的高发病率和转移潜力。基质金属蛋白酶（matrix metalloproteinases，MMPs）降解细胞外基质与癌细胞侵袭有关，因此，通过合成和天然抑制剂抑制MMPs可能在HCC治疗中具有重要意义。褪黑激素是松果体的主要产物，在HepG 2人肝细胞中发挥抗增殖、促凋亡和抗血管生成的特性，并通过抑制MMP-9在不同肿瘤类型中的酶活性而表现出抗侵袭和抗转移活性。然而，HCC模型中抗侵袭活性的潜在机制尚未完全阐明。在这里，我们证明，1毫米褪黑激素剂量降低IL-1诱导的HepG 2细胞MMP-9明胶酶活性，并通过下调MMP-9基因表达和上调MMP-9特异性抑制剂组织金属蛋白酶抑制剂（TIMP）-1抑制细胞侵袭和运动。MMP-2的表达和活性没有显著变化，MMP-2是与基质胶原降解有关的其他蛋白酶，其组织抑制剂TIMP-2也没有显著变化。此外，褪黑激素显着抑制IL-1诱导的核因子-κ B（NF-B）易位和转录活性。总之，我们证明褪黑激素调节运动性和侵袭性的HepG 2细胞在体外通过一个分子机制，涉及TIMP-1上调和衰减MMP-9的表达和活性，通过NF-B信号通路抑制。
Hepatocellular carcinoma (HCC) is one of the most lethal human cancers worldwide because of its high incidence and its metastatic potential. Extracellular matrix degradation by matrix metalloproteinases (MMPs) has been connected with cancer cell invasion, and it has been suggested that inhibition of MMPs by synthetic and natural inhibitors may be of great importance in the HCC therapies. Melatonin, the main product of the pineal gland, exerts antiproliferative, proapoptotic, and antiangiogenic properties in HepG2 human hepatocellular cells, and exhibits anti-invasive and antimetastatic activities by suppressing the enzymatic activity of MMP-9 in different tumor types. However, the underlying mechanism of anti-invasive activity in HCC models has not been fully elucidated. Here, we demonstrate that 1mm melatonin dosage reduced in IL-1-induced HepG2 cells MMP-9 gelatinase activity and inhibited cell invasion and motility through downregulation of MMP-9 gene expression and upregulation of the MMP-9-specific inhibitor tissue inhibitor of metalloproteinases (TIMP)-1. No significant changes were observed in the expression and activity of MMP-2, the other proteinase implicated in matrix collagen degradation, and its tissue inhibitor, TIMP-2. Also, melatonin significantly suppressed IL-1-induced nuclear factor-kappaB (NF-B) translocation and transcriptional activity. In summary, we demonstrate that melatonin modulates motility and invasiveness of HepG2 cell in vitro through a molecular mechanism that involves TIMP-1 upregulation and attenuation of MMP-9 expression and activity via NF-B signal pathway inhibition.