Abstract
BackgroundEpigallocatechin-3-gallate (EGCG) has been demonstrated to inhibit cancer in experimental studies through its antioxidant activity and modulations on cellular functions by binding specific proteins. We demonstrated previously that EGCG upregulates the expression of microRNA (i.e. miR-210) by binding HIF-1α, resulting in reduced cell proliferation and anchorage-independent growth. However, the binding affinities of EGCG to HIF-1α and many other targets are higher than the EGCG plasma peak level in experimental animals administered with high dose of EGCG, raising a concern whether the microRNA regulation by HIF-1α is involved in the anti-cancer activity of EGCG in vivo.ResultsWe employed functional genomic approaches to elucidate the role of microRNA in the EGCG inhibition of tobacco carcinogen-induced lung tumors in A/J mice. By analysing the microRNA profiles, we found modest changes in the expression levels of 21 microRNAs. By correlating these 21 microRNAs with the mRNA expression profiles using the computation methods, we identified 26 potential targeted genes of the 21 microRNAs. Further exploration using pathway analysis revealed that the most impacted pathways of EGCG treatment are the regulatory networks associated to AKT, NF-κB, MAP kinases, and cell cycle, and the identified miRNA targets are involved in the networks of AKT, MAP kinases and cell cycle regulationConclusionsThese results demonstrate that the miRNA-mediated regulation is actively involved in the major aspects of the anti-cancer activity of EGCG in vivo.
Highlights
Epigallocatechin-3-gallate (EGCG) has been demonstrated to inhibit cancer in experimental studies through its antioxidant activity and modulations on cellular functions by binding specific proteins
A/J mice treated with tobacco carcinogen such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) or benzo[a]pyrene (B[a]P) develop lung adenoma within 20 weeks, and these tumors begin to progress to adenocarcinoma after 20 weeks [17,18,19]
Since we and others have demonstrated that EGCG can prevent lung carcinogenesis and inhibit lung cancer growth [2], we explored whether the cellular changes in lung cancer cells treated with EGCG are associated with alteration in miRNA expression
Summary
Epigallocatechin-3-gallate (EGCG) has been demonstrated to inhibit cancer in experimental studies through its antioxidant activity and modulations on cellular functions by binding specific proteins. When 0.5% green tea polyphenol extract was given to the NNK-treated A/J mice as drinking fluid for 32 weeks, the progression of adenoma to adenocarcinoma was inhibited [19] This result was consistent with EGCG inhibiting the growth of the xenograft tumors of human lung cancer cell lines H1299 and H460 in nude mice [20]. Cell cycle regulation and inflammation were found to be the most impacted pathways by EGCG [21], suggesting that the anti-cancer activity of green tea polyphenols is mediated by inhibiting cell proliferation and anti-inflammation These inhibitions are likely to be combinatory effects resulted from changes in the expressions of multiple genes induced by the green tea polyphenols [21]
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