Green tea polyphenol EGCG suppresses lung cancer cell growth through upregulating miR-210 expression caused by stabilizing HIF-1 

Abstract

(-)-Epigallocatechin-3-gallate (EGCG) has been reported to affect many cellular regulatory pathways. This study aims to determine whether EGCG could target microRNA (miRNA), one of the mechanisms for cells to achieve subtle change in multiple targets. We found that, in both human and mouse lung cancer cells in culture, EGCG specifically upregulated the expression of miR-210, a major miRNA regulated by HIF-1α. Furthermore, we found that overexpression of miR-210 led to reduced cell proliferation rate and anchorage-independent growth as well as reduced sensitivity to EGCG. On the mechanisms of miR-210 regulation by EGCG, we demonstrated that the regulation was mediated through the hypoxia-response element in miR-210 promoter. Consistently, the upregulation of miR-210 was found to be correlated with the stabilized HIF-1α in lung cancer cell lines after EGCG treatment. This EGCG-induced stabilization of HIF-1α was further shown by the stabilization of HA-tagged HIF-1α but not the P402A/P564A-mutated HIF-1α by EGCG, suggesting that EGCG targets the oxygen-dependent degradation (ODD) domain. Direct evidence was obtained by affinity binding assay showing that EGCG specifically binds HIF-1α with a K(d) = 3.47 μM. This result suggests that EGCG binding interferes with the hydroxylation of key Pro residues in the ODD domain, preventing HIF-1α from the Pro hydroxylation-dependent ubiquitination and subsequent proteosome-mediated degradation. In summary, our results demonstrated, for the first time, the elevation of miR-210 by EGCG in lung cancer cell lines and this is mediated by the stabilization of HIF-1α. This event contributes to the anticancer activity of EGCG.

A derivative of epigallocatechin‐3‐gallate induces apoptosis via SHP‐1‐mediated suppression of BCR‐ABL and STAT3 signalling in chronic myelogenous leukaemia

“…Similarly, EGCG from green tea has been shown to exert potent anti-tumour activity in several types of leukaemia (Lung et al, 2002;Lee et al, 2004), prostate cancer (Siddiqui et al, 2011;Lee et al, 2012), cervical cancer (Ahn et al, 2003), colon cancer (Shimizu et al, 2005), lung cancer (Milligan et al, 2009;Wang et al, 2011;Liu et al, 2012), breast cancer (Sen and Chatterjee, 2011) and pancreatic cancer (Tang et al, 2012). However, clinical application of EGCG has been hampered by its limited solubility and efficacy in patients with cancer, underlining the need for the development of potent EGCG derivatives with improved metabolic stability and greater anti-cancer efficacy.…”

“…Epigallocatechin-3-gallate (EGCG), a major component of green tea polyphenols, has antioxidant (Hu et al, 2009), anti-inflammatory (Peairs et al, 2010), and anti-tumour (Davenport et al, 2010;Wang et al, 2011;Lee et al, 2012;Tang et al, 2012) activity in various cancer cells through the regulation of major cell signalling proteins such as the EGF receptor (Masuda et al, 2001;Ma et al, 2014) and STAT3. EGCG interacts directly with the STAT3 SH2 domain (Wang et al, 2013) to stimulate caspase activation (Gupta et al, 2004).…”

HIF-1α-induced microRNA-210 reduces hypoxia-induced osteoblast MG-63 cell apoptosis

“…39,42) microRNA-210 in particular, has been well studied for its effects in rescuing cardiac function after myocardial infarcts via the upregulation of angiogenesis and inhibition of cardiomyocyte apoptosis. 45) Recent years, accumulated data show that it is significantly upregulated in various kinds of tumors, such as Head and Neck Paragangliomas, 46) lung cancer cells, 47) breast cancer cells. 48) Previous report revealed that overexpression of microRNA-210 could promote the survival of mesenchymal stem cells (MSCs) exposed to hypoxia.…”

Dietary flaxseed modulates the miRNA profile in irradiated and non-irradiated murine lungs

“…42 miRNAs can be modulated by botanicals in lung cancer. [43][44][45][46] The effects of curcumin on a human retinal pigment epithelial cell line, ARPE-19, included downregulation of 20 and upregulation of 9 miRNAs. 47 Effects of resveratrol on miRNA have also been studied.…”