Roles of Dietary Phytoestrogens on the Regulation of Epithelial-Mesenchymal Transition in Diverse Cancer Metastasis

Abstract

Epithelial-mesenchymal transition (EMT) plays a key role in tumor progression. The cells undergoing EMT upregulate the expression of cell motility-related proteins and show enhanced migration and invasion. The hallmarks of EMT in cancer cells include changed cell morphology and increased metastatic capabilities in cell migration and invasion. Therefore, prevention of EMT is an important tool for the inhibition of tumor metastasis. A novel preventive therapy is needed, such as treatment of natural dietary substances that are nontoxic to normal human cells, but effective in inhibiting cancer cells. Phytoestrogens, such as genistein, resveratrol, kaempferol and 3,3′-diindolylmethane (DIM), can be raised as possible candidates. They are plant-derived dietary estrogens, which are found in tea, vegetables and fruits, and are known to have various biological efficacies, including chemopreventive activity against cancers. Specifically, these phytoestrogens may induce not only anti-proliferation, apoptosis and cell cycle arrest, but also anti-metastasis by inhibiting the EMT process in various cancer cells. There have been several signaling pathways found to be associated with the induction of the EMT process in cancer cells. Phytoestrogens were demonstrated to have chemopreventive effects on cancer metastasis by inhibiting EMT-associated pathways, such as Notch-1 and TGF-beta signaling. As a result, phytoestrogens can inhibit or reverse the EMT process by upregulating the expression of epithelial phenotypes, including E-cadherin, and downregulating the expression of mesenchymal phenotypes, including N-cadherin, Snail, Slug, and vimentin. In this review, we focused on the important roles of phytoestrogens in inhibiting EMT in many types of cancer and suggested phytoestrogens as prominent alternative compounds to chemotherapy.

MiR‐101‐3p Regulates the Viability of Lung Squamous Carcinoma Cells via Targeting EZH2

“…For cell cycle, the early literature has also confirmed that EZH2 contributed to accumulation of cells in the S phase while reduced the cell in G1 phase [Bachmann et al, ]. Additionally, the increased cell invasion and migration were related to the down‐regulated E‐cadherin and up‐regulated vimentin [Lee et al, ]. In our experiments, we found that the knockdown of EZH2 by transfecting siRNA‐ EZH2 , the expression of cyclin D1 , NOTCH1 , β‐catenin , and vimentin protein was obviously reduced while that of E‐cadherin protein was promoted compared with the control group.…”

Reversal of Epithelial–Mesenchymal Transition by Natural Anti-Inflammatory and Pro-Resolving Lipids

“…Genistein first isolated from Genista tinctoria can suppress psoriasis-related inflammation through a STAT3/NF-κB-dependent mechanism in keratinocytes [172,173]. For more detailed information about genistein's anti-inflammatory action or anti-EMT, please refer to a previous review by Spagnulo et al and Lee et al [174,175]. Genistein (200 µM) can induce apoptosis of colon cancer cells by reversal of EMT via a notch1/NF-κB/slug/E-cadherin pathway [176].…”

Hormonally active phytochemicals and vertebrate evolution

“…In frogs and rats, genistein alters thyroid hormone signaling and thyroid morphology and reduces thyroid hormone receptor transcription (Ji et al., ; Sosić‐Jurjević et al., ). In cancer models, genistein limits metastasis by inhibiting Notch‐1 and TGF‐beta signaling and promoting tumor cell apoptosis (Lee, Hwang, & Choi, ; Liu‐Smith & Meyskens, ). It is remarkable that one molecule can influence physiological function in plants and animals through such diverse mechanisms with a variety of outcomes.…”

“…Interestingly, closely related species can exhibit different levels of receptor activation by HAPs, as shown for southern white rhinoceros and one‐horned rhinoceros (Tubbs, Hartig, Cardon, Varga, & Milnes, ). HAPs also participate in nongenomic signaling pathways that alter phosphorylation reactions, enzymatic activity, and second messenger cascades (Greathouse et al., ; Lee et al., ). A recent survey of eleven plant species in Uganda found that extracts of leaves, bark, or flowers showed varying degrees of receptor binding in estradiol, progesterone, androgen, and cortisol assays (Wasserman et al., ).…”