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Inhibition of matrix metalloproteinase‐9 and nuclear factor kappa B contribute to melatonin prevention of motility and invasiveness in H ep G 2 liver cancer cells
Author(s) -
Ordoñez Raquel,
CarbajoPescador Sara,
PrietoDominguez Néstor,
GarcíaPalomo Andrés,
GonzálezGallego Javier,
Mauriz José L.
Publication year - 2014
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12092
Subject(s) - downregulation and upregulation , melatonin , matrix metalloproteinase , motility , tissue inhibitor of metalloproteinase , extracellular matrix , gelatinase , biology , cancer research , endocrinology , microbiology and biotechnology , biochemistry , gene
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 ( MMP s) has been connected with cancer cell invasion, and it has been suggested that inhibition of MMP s 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 H ep G 2 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 1 m m melatonin dosage reduced in IL ‐1β‐induced H ep G 2 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 ‐1β‐induced nuclear factor‐kappa B ( NF ‐κB) translocation and transcriptional activity. In summary, we demonstrate that melatonin modulates motility and invasiveness of H ep G 2 cell in vitro through a molecular mechanism that involves TIMP ‐1 upregulation and attenuation of MMP ‐9 expression and activity via NF ‐κB signal pathway inhibition.