TGF-β-Mediated Epithelial-Mesenchymal Transition and Cancer Metastasis

Abstract

Transforming growth factor β (TGF-β) is a secreted cytokine that regulates cell proliferation, migration, and the differentiation of a plethora of different cell types. Consistent with these findings, TGF-β plays a key role in controlling embryogenic development, inflammation, and tissue repair, as well as in maintaining adult tissue homeostasis. TGF-β elicits a broad range of context-dependent cellular responses, and consequently, alterations in TGF-β signaling have been implicated in many diseases, including cancer. During the early stages of tumorigenesis, TGF-β acts as a tumor suppressor by inducing cytostasis and the apoptosis of normal and premalignant cells. However, at later stages, when cancer cells have acquired oncogenic mutations and/or have lost tumor suppressor gene function, cells are resistant to TGF-β-induced growth arrest, and TGF-β functions as a tumor promotor by stimulating tumor cells to undergo the so-called epithelial-mesenchymal transition (EMT). The latter leads to metastasis and chemotherapy resistance. TGF-β further supports cancer growth and progression by activating tumor angiogenesis and cancer-associated fibroblasts and enabling the tumor to evade inhibitory immune responses. In this review, we will consider the role of TGF-β signaling in cell cycle arrest, apoptosis, EMT and cancer cell metastasis. In particular, we will highlight recent insights into the multistep and dynamically controlled process of TGF-β-induced EMT and the functions of miRNAs and long noncoding RNAs in this process. Finally, we will discuss how these new mechanistic insights might be exploited to develop novel therapeutic interventions.

Epiregulin promotes trophoblast epithelial–mesenchymal transition through poFUT1 and O‐fucosylation by poFUT1 on uPA

“…33 Autocrine TGFβ/TGFβR signalling can stimulate the EMT in the cancer cells. 34 Our results also provided the evidence that poFUT1, epiregulin and uPA were expressed at lower levels in trophoblast from abortion patients ( Figure 1A Epiregulin is secreted by early human placenta and uterine glands. [9][10][11] Epiregulin is a member of the EGF family, which are involved in many physiological and pathological processes, such as oocyte maturation, cutaneous wound healing and vascular remodelling.…”

“…MMP14 activation is critical for EMT and migration by regulating the levels of cadherins in the cells . Autocrine TGFβ/TGFβR signalling can stimulate the EMT in the cancer cells . Our results also provided the evidence that poFUT1, epiregulin and uPA were expressed at lower levels in trophoblast from abortion patients (Figure A) than normal pregnant women, and decreased level of these molecules could hamper embryo implantation by interfering the trophoblast EMT process.…”

Circular RNA cESRP1 sensitises small cell lung cancer cells to chemotherapy by sponging miR-93-5p to inhibit TGF-β signalling

“…Many studies have shown that TGF-β can serve as a tumour suppressors to induce the expression of Smad7 and p21(CDKN1A) in certain cancers [55][56][57]. Interestingly, Smad7 and p21(CDKN1A) may act as components in a negative feedback regulation of TGF-β signalling, as Smad7 impedes TGF-β/Smad-driven transcription [21,58,59].…”

Fangjihuangqi Decoction inhibits MDA‐MB‐231 cell invasion in vitro and decreases tumor growth and metastasis in triple‐negative breast cancer xenografts tumor zebrafish model

“…After cell adhesion loss, cell polarity changes from apical‐substrate polarity to anterior‐posterior polarity, triggering cell migration and enhancing invasiveness. Epithelial‐mesenchymal transition as a new target of prime interest for anticancer metastasis and chemoresistance in breast cancer therapy has drawn great attention . Studies have shown that EMT biomarkers play a key role in breast cancer metastasis.…”

“…Epithelial-mesenchymal transition as a new target of prime interest for anticancer metastasis and chemoresistance in breast cancer therapy has drawn great attention. 20,21 Studies have shown that EMT biomarkers play a key role in breast cancer metastasis. Families of the zinc-finger protein Snails (Snail1, Snail2, Snail3), the E-box-binding proteins Zebs (Zeb1, Zeb2), the basic helix-loop-helix protein Twists (Twist1, Twist2) directly inhibit the expression of E-cadherin in breast cells by directly binding to E-box of the proximal promoter of CDH1.…”