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Review
. 2015 May;106(5):481-8.
doi: 10.1111/cas.12630. Epub 2015 Mar 9.

Epithelial-mesenchymal transition is regulated at post-transcriptional levels by transforming growth factor-β signaling during tumor progression

Masao Saitoh  1
Affiliations
Review

Epithelial-mesenchymal transition is regulated at post-transcriptional levels by transforming growth factor-β signaling during tumor progression

Masao Saitoh. Cancer Sci. 2015 May.

Abstract

Transforming growth factor (TGF)-β acts as a tumor suppressor during cancer initiation, but as a tumor promoter during tumor progression. It has become increasingly clear that TGF-β plays fundamental roles in multiple steps of tumor progression, including epithelial-mesenchymal transition (EMT). The EMT, first described by developmental biologists at the beginning of the 1980s, plays crucial roles in appropriate embryonic development, but also functions in adults during wound healing, organ fibrosis, and tumor progression. During EMT, epithelial cells lose their epithelial polarity and acquire mesenchymal phenotypes, endowing them with migratory and invasive properties. Many secreted polypeptides are implicated in this process, and act in a sequential or cooperative manner. TGF-β induces EMT by propagating intracellular signaling pathways and activating transcriptional factors. Here, I discuss new insights into the molecular mechanisms underlying induction of EMT by TGF-β in cooperation with Ras or growth factors, along with the signals that induce EMT through transcriptional and post-transcriptional regulation.

Keywords: Cancer biology; EMT; Smad; TGF-β; signal transduction.

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Figures

Fig 1
Fig 1
Features of epithelial–mesenchymal transition (EMT).
Fig 2
Fig 2
Induction of the epithelial–mesenchymal transition (EMT) by transforming growth factor (TGF)-β through transcriptional regulation of miRNAs and transcription factors. TGF-β directly or indirectly upregulates the key EMT regulators at the transcriptional level, and appears to modulate expression of miRNAs that target the key EMT regulators. δEF1, δ-crystallin/E2-box factor 1; EGF, epidermal growth factor; HMGA2, high mobility group AT-hook 2; ZEB1, zinc finger E-box binding homeobox 1.
Fig 3
Fig 3
Schematic illustrations of a double-negative feedback loop and the ceRNA pathway. Expression levels of the key EMT regulators and miRNAs suppress each other. Some of the key EMT regulators function as ceRNAs. δEF1, δ-crystallin/E2-box factor 1; HMGA2, high mobility group AT-hook 2; PTEN, phosphatase and tensin homolog; SIP1, Smad-interacting protein 1; TGF-β, transforming growth factor-β; ZEB1, zinc finger E-box binding homeobox 1.
Fig 4
Fig 4
EMT by TGF-β in cooperation with FGF-2 or oncogenic K-Ras. (a) Treatment with both TGF-β and FGF-2 dramatically enhanced epithelial–mesenchymal transition, as determined by phalloidin staining. (b) When K-Ras was knocked down with the siRNA in Panc-1 cells harboring an endogenous oncogenic K-Ras mutation, TGF-β-induced Snail expression was reduced. (c) When RasG12V was transfected into HeLa cells harboring wild-type Ras, Snail (shown in blue) was synergistically upregulated by TGF-β, whereas Smad7 (shown in red), a representative target gene of TGF-β, was slightly inhibited.
Fig 5
Fig 5
Schematic illustrations of epithelial–mesenchymal transition (EMT) regulated by transcriptional and post-transcriptional mechanisms. The key EMT regulators decrease expression of epithelial splicing regulatory proteins (ESRPs), leading to changes in alternative splicing events. FGFR, fibroblast growth factor receptor; FSP, fibroblast-specific protein; SMA, smooth muscle α-actin; ZEB, zinc finger E-box binding homeobox.
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