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Review
. 2019 Sep 20;8(10):1118.
doi: 10.3390/cells8101118.

The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges

Chin-Yap Loh  1 , Jian Yi Chai  2 , Ting Fang Tang  3 , Won Fen Wong  4 , Gautam Sethi  5 , Muthu Kumaraswamy Shanmugam  6 , Pei Pei Chong  7 , Chung Yeng Looi  8
Affiliations
Review

The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges

Chin-Yap Loh et al. Cells. .

Abstract

Epithelial-to-Mesenchymal Transition (EMT) has been shown to be crucial in tumorigenesis where the EMT program enhances metastasis, chemoresistance and tumor stemness. Due to its emerging role as a pivotal driver of tumorigenesis, targeting EMT is of great therapeutic interest in counteracting metastasis and chemoresistance in cancer patients. The hallmark of EMT is the upregulation of N-cadherin followed by the downregulation of E-cadherin, and this process is regulated by a complex network of signaling pathways and transcription factors. In this review, we summarized the recent understanding of the roles of E- and N-cadherins in cancer invasion and metastasis as well as the crosstalk with other signaling pathways involved in EMT. We also highlighted a few natural compounds with potential anti-EMT property and outlined the future directions in the development of novel intervention in human cancer treatments. We have reviewed 287 published papers related to this topic and identified some of the challenges faced in translating the discovery work from bench to bedside.

Keywords: E-cadherin; Epithelial-to-Mesenchymal Transition; N-cadherin; natural compounds; signaling pathways.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of E-cadherin and N-cadherin. E-cadherin and N-cadherin are classical cadherins and share similar structures. They form cadherin-catenin complex where the cytoplasmic domain consists of EC repeats that bind with catenins to moderate the cytoskeletal filament containing actin. The structural difference between E-cadherin and N-cadherin is that E-cadherin binds with the shorter isoform of p120 catenin while N-cadherin binds with the longer isoform. Abbreviations: EC = extracellular cadherin; ctn: catenin.
Figure 2
Figure 2
Functions of E-cadherin and N-cadherin. E-cadherin junctions form the stable adherens junction and enable strong cell–cell contact. As p120 catenin and β-catenin are strongly bound to the E-cadherin complex, they are not available to activate Wnt/β-catenin pathway and P13K pathway. N-cadherin junction enables the stabilization of fibroblast growth factor receptor (FGFR) which leads to activation of MAPK/ERK pathway and activates the PI3K pathway in association with PDGFR to enhance cell survival and migration. Abbreviations: PI3K = Phosphoinositide-3-kinase; RAC = Ras-related C3 Botulinum Toxin Substrate; GSK3 = Glycogen Synthase Kinase 3; TCF = T-cell Factor; PDGFR: Platelet-derived Growth Factor Receptor; FGFR: Fibroblast Growth Factor Receptor; MAPK = Mitogen-activated Protein Kinase; ERK = Extracellular Signal-regulated Kinases.
Figure 3
Figure 3
“Cadherin switching” is the downregulation of E-cadherins and upregulation of N-cadherins in EMT. E-cadherin-mediated adherens junctions disassociate due to the downregulation of E-cadherin while N-cadherin junctions establish a relatively weak adherens junction. Several signaling pathways such as Wnt/β-catenin, PI3K/AKT, TCF/lymphoid enhancer-binding factor (LEF) and RhoA will be activated by β-catenin following the loss of E-cadherin. Increased expression of RAC, cell division control protein 42 homolog (Cdc42), and RhoA leads to the rearrangement of cytoskeleton, whereby consequently the cell is changed from an adhesive state into motile state. Abbreviations: LEF = Lymphoid Enhancer-Binding Factor; RhoA = Ras Homolog Gene Family, member A; ROCK = Rho-associated, coiled-coil containing Protein Kinase; Cdc42 = Cell Division Control Protein 42 Homolog.
Figure 4
Figure 4
Signaling pathways involved in Epithelial-to-Mesenchymal Transition. Crosstalk between multiple signaling pathways increase the expression of EMT transcription factors including SNAI1, SLUG, TWIST, and ZEB leads to loss of epithelial characteristics and gain of mesenchymal characteristics. Wnt/β-catenin pathway induces EMT by interacting with TCF/LEF. Growth factors including Epidermal Growth Factor (EGF), FGF and hepatocyte growth factor (HGF) bind to their respective receptors to activate RAS/ERK signaling, RAS/PI3K signaling, and RAS/RAC signaling. Activation of RAS/RAC pathway subsequently leads to reorganization of cytoskeleton by elevating the expression of RAC and Cdc42. Hippo pathway inhibits YAP/TAZ pathway and EMT, but it will be suppressed when PI3K and F-actin are upregulated by other signaling pathways during EMT. Hedgehog (HH)/GLI and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways increase SNAI1 expression and drive the EMT program. TGF-β pathway promotes EMT via either Smad or non-Smad signaling. TGF-β/Smad signaling activates Smad2/3 complex where the complex can interact with transcription factors in the nucleus to drive EMT, activates p38 MAPK pathway and increases the expression of HMGA2 to upregulate N-cadherin. Non-Smad signaling activates PI3K/AKT signaling to induce EMT by suppressing GSK3 and promoting the expression of NF-κB. NCID cleaved by activated Notch pathway will translocate into the nucleus to increase SLUG expression. N-cadherin upregulates the expression of RhoA to strengthen the cell–cell junction and enforce cytoskeleton rearrangement. Abbreviations: IL = Interleukin; LATS = Large Tumor Suppressor; NCID = Notch intracellular cytoplasmic domain; Rho = Ras homolog; PAK = Serine/threonine-protein Kinase; YAP = Yes-associated Protein; MEK = Mitogen-activated Protein Kinase; PTCH = Patched; SMO = Smoothened; SUFU = Suppressor of Fused Homolog; GLI 1 = Glioma-associated oncogene; JAK = Janus kinase; STAT = Signal Transducer and Activator of Transcription; NF-κB = Nuclear Factor Kappa-light-chain-enhancer of Activated B cells; HMGA2 = High mobility group A2; EGF: Epidermal Growth Factor.
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