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.
Highlights
Phytochemicals are chemical compounds that occur naturally in plants, amounting to as many as 4000 different chemicals
Expression of the miR-200 family was increased or decreased in the process of metastasis: miR-200 was downregulated in the Epithelial-mesenchymal transition (EMT) process, while it was upregulated during the re-epithelialization of distal metastasis [82]
Since the dysregulation of proteins in signaling pathways involved in EMT is associated with cancer progression, they could be potentially targeted as prognostic markers or therapeutic targets of cancer metastasis [83]
Summary
Phytochemicals are chemical compounds that occur naturally in plants, amounting to as many as 4000 different chemicals. At present, inhibiting human carcinogenesis using plant-derived compounds is considered as a vital and urgent challenge, despite some phytochemicals having been used for targeting many forms of cancer as major sources of highly effective conventional drugs [4,5,6]. Phytoestrogens are generally classified into four main classes: isoflavones (genistein, daidzein, kaempferol), lignans (secoisolariciresinol, matairesinol, pinoresinol, lariciresinol), coumestan (coumestrol) and stilbenes (resveratrol) [23,24]. Genistein, kaempferol and resveratrol are phenolic compounds: genistein and kaempferol are isoflavones, having a common flavone structure; resveratrol is a derivative of diphenylethane; and DIM is an active indole compound originated from indole-3-carbinol (I3C), an inactive form of indole They are actively-studied phytoestrogens that have great potential to display anti-cancer effects.
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