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Review
. 2020 Feb 28;12(3):555.
doi: 10.3390/cancers12030555.

The Role of Carcinogenesis-Related Biomarkers in the Wnt Pathway and Their Effects on Epithelial-Mesenchymal Transition (EMT) in Oral Squamous Cell Carcinoma

Yunpeng Bai  1 , Jingjing Sha  1 , Takahiro Kanno  1
Affiliations
Review

The Role of Carcinogenesis-Related Biomarkers in the Wnt Pathway and Their Effects on Epithelial-Mesenchymal Transition (EMT) in Oral Squamous Cell Carcinoma

Yunpeng Bai et al. Cancers (Basel). .

Abstract

As oral squamous cell carcinoma (OSCC) can develop from potentially malignant disorders (PMDs), it is critical to develop methods for early detection to improve the prognosis of patients. Epithelial-mesenchymal transition (EMT) plays an important role during tumor progression and metastasis. The Wnt signaling pathway is an intercellular pathway in animals that also plays a fundamental role in cell proliferation and regeneration, and in the function of many cell or tissue types. Specific components of master regulators such as epithelial cadherin (E-cadherin), Vimentin, adenomatous polyposis coli (APC), Snail, and neural cadherin (N-cadherin), which are known to control the EMT process, have also been implicated in the Wnt cascade. Here, we review recent findings on the Wnt signaling pathway and the expression mechanism. These regulators are known to play roles in EMT and tumor progression, especially in OSCC. Characterizing the mechanisms through which both EMT and the Wnt pathway play a role in these cellular pathways could increase our understanding of the tumor genesis process and may allow for the development of improved therapeutics for OSCC.

Keywords: EMT; OSCC; PMD; WNT; biomarker.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Non-canonical Wnt pathway: Wnt signaling activates another mechanism independent of β-catenin. Based on the downstream molecules activated, the non-canonical Wnt signaling can be further classified into several categories: 1. Wnt-planar cell polarity (PCP) signaling; 2. Wnt-cyclic guanosine monophosphate (cGMP)/calcium (Ca2+) signaling; 3. Wnt-small GTPase (RAP1) signaling; 4. Wnt-receptor tyrosine kinase-like orphan receptor 2 (ROR2) signaling; 5. Wnt-protein kinase A (PKA) signaling; 6. Wnt-glycogen synthase kinase 3 (GSK3)-microtubule (MT) signaling. 7. Wnt-atypical protein kinase C (aPKC) signaling; 8. Wnt-receptor-like tyrosine kinase (RYK) signaling; and 9. Wnt-mammalian target of rapamycin (mTOR) signaling [30,31,32,33].
Figure 2
Figure 2
The inactivated Wnt pathway and the activated canonical Wnt pathway. (a) Inactivated Wnt pathway. In the absence of the Wnt ligand, cytoplasmic β-catenin is phosphorylated by glycogen synthase kinase 3β (GSK-3β) within a destruction complex that includes Axin, adenomatous polyposis coli (APC) protein, and casein kinase 1 (CK1). Phosphorylated β-catenin is directly ubiquitinated by the β-transducin repeat-containing protein (β-TrCP) E3 ligase and degraded by the 26 S proteasome pathway. Thus, the Wnt pathway is repressed due to a lack of β-catenin translocation into the nucleus [43]. (b) Activated canonical Wnt pathway. The Wnt ligand binds to its Frizzled (Fzd) receptor and lipoprotein-related protein (LRP) coreceptor, resulting in activation of the Disheveled (DSH) protein, which in turn destabilizes the destruction complex and leads to β-catenin stabilization via dephosphorylation. The stabilized β-catenin accumulates in the cytoplasm and translocates into the nucleus, where it interacts with the T-cell factor/lymphocyte enhancer factor (TCF/LEF) of the transcriptional complex to induce the expression of downstream genes, such as c-Myc, cyclin D1, matrix metalloproteinase 1 (MMP-1), and MMP-7 [44,45,46].
Figure 3
Figure 3
The extracellular domain consists of five cadherin-type repeats bound together by calcium ions, forming a parallel cadherin dimer. In the cytoplasmic domain, the core universal-catenin complex consists of p120 catenin bound to the juxta-membrane region, and β-catenin, bound to the distal region, which in turn binds α-catenin; α-catenin then binds through actin or actin-binding proteins [55,56]. In contrast, while epidermal growth factor (EGF) binds to its receptor (EGFR) and activates EGFR, the phosphorylation of β-catenin and GSK-3β are induced. This leads to dissociation of β-catenin from the cadherin-catenin protein complex and translocation into the nucleus (phosphorylated GSK-3β also induces uncoupling of β-catenin from the destruction complex and translocation into the core through the canonical Wnt signaling pathway). Consequently, nuclear β-catenin binds with TCF/LEF and induces the transcription of the Wnt target gene, which affects the cell cycle, migration, and invasion [56,57].
Figure 4
Figure 4
Secreted Frizzled-related protein-1 (SFRP1) is a suppressor of Wnt protein that binds to Wnt protein in a competitive manner that prevents binding with the transmembrane Fzd receptor. With decreased SFRP1 expression, the Wnt protein associates with the Fzd receptor, after which the Wnt pathway is activated. The active Wnt pathway induces β-catenin destruction through the E-cadherin complex and translocation to the nucleus where it can interact with TCF/LEF and activate the Vimentin promoter. Vimentin is then synthesized and released into the extracellular matrix [64,65].
Figure 5
Figure 5
In cells where exit from the cell cycle is induced by serum starvation or high cell density, APC is mainly expressed in the cytoplasm. APC accumulates in the nucleus in cells with high Ki-67 expression. APC is known to translocate from the cytoplasm into the nucleus in cells with an increased degree of differentiation [81,85]. Nuclear accumulation of APC also occurs simultaneously with high Vimentin expression and destruction of the E-cadherin complex. A: Epithelial cells with a lower cell proliferation rate. B: Epithelial cells with a higher proliferation rate.
Figure 6
Figure 6
Upregulation of Snail protein expression is accompanied by the accumulation of β-catenin in the nucleus, reduction of E-cadherin expression, and increased Vimentin expression. This is suggestive of EMT. During PMD in OSCC, the enhanced expression of Snail is an indicator of increased cell invasion and migration [111].
Figure 7
Figure 7
In specific cell types such as prostate [118,119], nasopharyngeal [120], breast [121], and ovarian cells [122], suppression of E-cadherin and overexpression of N-cadherin can occur, a phenomenon called E-cadherin/N-cadherin “switching”. A: Conceptual image of the E-cadherin/N-cadherin switch. B: In normal tissue, due to the intercellular bridge consisting of the desmosome, adherent proteins, such as E-cadherin, microvilli, and the epithelial cells are associated through a tight junction, forming the basement membrane. C: In PMDs, the intercellular junction loosens, parts of the junction and desmosome dissociate, apical-basal polarity is lost, atypical cells increase in number, and cell migration increase. In PMDs, the basement membrane becomes irregular. At the end of the PMD stage, some epithelial cells invade into deeper layers by passing through the basement membrane. D: In OSCCs, atypical epithelial cells increase significantly, and cell polarity is lost with nuclear expansion. At this time, the basement membrane is degraded, and cells can invade and migrate into a very deep layer. In front of the lesion, cells lose epithelial characteristics but gain mesenchymal features. In addition, mesenchymal markers such as Vimentin, Snail, and N-cadherin, are upregulated.
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References

    1. Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45:309–316. doi: 10.1016/j.oraloncology.2008.06.002. - DOI - PubMed
    1. Chaw S.Y., Abdul Majeed A., Dalley A.J., Chan A., Stein S., Farah C.S. Epithelial to mesenchymal transition (EMT) biomarkers—E-cadherin, beta-catenin, APC and Vimentin—In oral squamous cell carcinogenesis and transformation. Oral Oncol. 2012;48:997–1006. doi: 10.1016/j.oraloncology.2012.05.011. - DOI - PubMed
    1. Glazer C.A., Chang S.S., Ha P.K., Califano J.A. Applying the molecular biology and epigenetics of head and neck cancer in everyday clinical practice. Oral Oncol. 2009;45:440–446. doi: 10.1016/j.oraloncology.2008.05.013. - DOI - PubMed
    1. Siu A., Lee C., Dang D., Lee C., Ramos D.M. Stem cell markers as predictors of oral cancer invasion. Anticancer Res. 2012;32:1163–1166. - PubMed
    1. Woolgar J.A., Triantafyllou A. Pitfalls and procedures in the histopathological diagnosis of oral and oropharyngeal squamous cell carcinoma and a review of the role of pathology in prognosis. Oral Oncol. 2009;45:361–385. doi: 10.1016/j.oraloncology.2008.07.016. - DOI - PubMed