Abstract
BackgroundHepatocellular carcinoma (HCC) is the most common malignant tumor of the adult liver, exhibiting rapid progression and poor prognosis. Chlorogenic acid (CGA), a polyphenol, has several biological activities, including the suppression of liver cancer cell invasion and metastasis. Increased levels or alterations in the function of DNMT1 are associated with the inactivation of tumor suppressor genes. However, the CGA-affected DNMT1 expression mediated mechanism is still unclear.MethodsThe human hepatocellular carcinoma (HCC) HepG2 cells were treated with a positive control drug (5-AZA) or varying doses of CGA. DNA methyltransferase 1 (DNMT1) protein levels and other relevant proteins were evaluated using Western blotting and immunocytochemistry. Cell-cycle analysis was performed by flow cytometry-based PI staining, and cell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The transwell invasion and wound healing assays were used to evaluate cell migration and invasion. In vivo proliferation of the HCC cells was detected. We investigated the expression of DNMT1, p53, p21, p-ERK, MMP-2, and MMP-9 in tumors using immunohistochemical analysis.ResultsOur results showed that CGA inhibited the proliferation, colony formation, invasion, and metastasis of HepG2 cells both in vitro and in vivo by down-regulating DNMT1 protein expression, which enhanced p53 and p21 activity, and resulting in a significant reduction in cell proliferation and metastasis. Moreover, CGA inactivated ERK1/2 and reduced MMP-2 and MMP-9 expression in HepG2 cells.ConclusionsCGA can suppress liver cancer cell proliferation, invasion, and metastasis through several pathways. CGA could serve as a candidate chemopreventive agent for HCC.
Highlights
Hepatocellular carcinoma (HCC) is the most common adult liver malignancy exhibiting rapid progression and poor prognosis (Shimada et al, 1996; Ma et al, 2014)
Our results showed that Chlorogenic acid (CGA) inhibited the proliferation, colony formation, invasion, and metastasis of HepG2 cells both in vitro and in vivo by down-regulating DNA methyltransferase 1 (DNMT1) protein expression, which enhanced p53 and p21 activity, and resulting in a significant reduction in cell proliferation and metastasis
DNA methylation is the addition of a methyl group to a cytosine (C) residue assisted by an enzyme, DNA methyltransferase 1 (DNMT1); it is the most prevalent epigenetic modification (Jones and Baylin, 2002; Hegi et al, 2009)
Summary
Hepatocellular carcinoma (HCC) is the most common adult liver malignancy exhibiting rapid progression and poor prognosis (Shimada et al, 1996; Ma et al, 2014). Epigenetic alterations are heritable variations that are not attributed to DNA sequence variations. Gene promoter hypermethylation has been considered as a vital mechanism to inhibit the expression of genes involved in tumor development. Roughly half the tumorsuppressor genes are reported to be inactivated by epigenetic rather than genetic mechanisms (Xu et al, 2018). Hepatocellular carcinoma (HCC) is the most common malignant tumor of the adult liver, exhibiting rapid progression and poor prognosis. Increased levels or alterations in the function of DNMT1 are associated with the inactivation of tumor suppressor genes. The CGA-affected DNMT1 expression mediated mechanism is still unclear
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