NPC tumor cells are very likely to invade surrounding tissue or metastasize to cervical lymph nodes in the early stages of tumor development [20
]. However, the major relevant mechanism remains unknown. Many factors may be involved in local invasion and distant metastasis, including cell–cell adhesion molecules, matrix metalloproteinase family and cytokines, which can alter the mobility and distribution of tumoral cells [21
β-Catenin contributes both to cell–cell adhesion and to the Wnt signaling pathway [23
]. The cadherin–catenin complex is a group of membrane proteins that is important in cell–cell adhesion, tumor suppression, cell differentiation and cell migration. Some reports have suggested that downregulated expression of β-catenin might play a role in early and late tumor invasion and metastasis [25
]. Downregulation of β-catenin has been found to be closely related to advanced clinical disease and short survival in NPC patients [12
]. The present study, however, noted no alteration in β-catenin protein expression, and no correlation between its expression and NPC patient outcomes. These results suggest that β-catenin may not in itself be a major factor for NPC tumor cell invasion and metastasis. Here, β-catenin protein levels were evaluated using inmunohistochemical staining, a semi-quantitative technique enabling assessment of proteins in paraffin-embedded tissues. Further research will evaluate β-catenin expression levels using the western blot technique, with a view to measuring possible alterations in β-catenin protein levels in fresh tissue.
β-Catenin is also involved in the Wnt canonical pathway as a transcriptional activator [23
]. The inhibition of glycogen synthase kinase (GSK-3β) and the adenomatous polyposis coli (APC) protein ultimately results in the stabilization and nuclear translocation of cytoplastic β-catenin. Finally, nuclear β-catenin interacts with various transcription factors to cause proliferation and differentiation. However, further research is required to link altered β-catenin levels and development of NPC. Here, β-catenin was detected in membrane and cytoplasm, but not in the nucleus. Although Zheng et al. [12
] found nuclear β-catenin in five cases of undifferentiated NPC, other authors have failed to detect nuclear β-catenin. Li et al. [27
] observed increased membrane β-catenin but no nuclear β-catenin in 42 NPC patients; by contrast, Zhi et al. [28
] found no nuclear or cytoplasmic β-catenin in any NPC tissues studied. In the present study, failure to detect nuclear β-catenin suggests that the canonical Wnt pathway may be inactivated in this type of cancer. However, this cannot be categorically confirmed, since stabilized β-catenin was detected in cytoplasm. Further research will be necessary to determine whether the Wnt pathway is activated by overexpression of its receptors or silencing of its suppressors, and also to investigate the possible activation of the non-canonical Wnt pathway that includes signaling through calcium flux, JNK and heterotrimeric G proteins.
E-cadherin is essential for normal cell function, and downregulated in processes such as wound healing, allowing epithelial cells to move and cover denuded tissue [29
]. E-cadherin, localized to the zonula adherens, complexes with catenins β and γ; β- and γ-catenins in turn bind to α-catenin which attaches to the actin filaments in the cell cytoskeleton [30
]. E-cadherin is thought to act as a tumor suppressor, since it suppresses invasion and metastasis [31
]. Low expression of E-cadherin has been shown to predict poor outcome in oral cavity and laryngeal carcinomas [32
]. In this study, moderate E-cadherin expression was detected in all type 1 and type 3 NPC tissues and in almost all type 2 tissues. By contrast, strong E-cadherin expression was detected in non-tumoral tissues, so that downregulation of E-cadherin expression in NPC tissues may indicate a greater capacity for invasion and metastasis. Indeed, a positive correlation was observed between E-cadherin expression levels, the presence of lymph node metastasis in NPC tissues and patient outcomes. In this respect, several studies have shown that diminished E-cadherin expression is a good predictor of concurrent lymph node metastasis in laryngeal carcinoma, and head and neck squamous cell cancer [34
]. Zhi et al. [28
] noted a correlation between reduced E-cadherin expression and NPC lymph node metastasis. In some cancer cells, aberrant gene promoter methylation of E-cadherin may be responsible for the decreased expression of E-cadherin [34
]; future research will therefore focus on possible epigenetic changes due to promoter hypermethylation in NPC tissues.
Finally, a correlation was observed between E-cadherin protein levels and β-catenin localization, low levels being associated with β-catenin in cytoplasm. Other studies of head and neck squamous cell carcinomas report loss of membranous E-cadherin and β-catenin expression and increased cytoplasmic expression, irrespective of the primary carcinoma or nodal carcinoma involved [37
]. Impairment of cell–cell adhesion is an essential step in the progression from localized malignancy to stromal and vascular invasion and metastatic disease. This impairment is achieved through a variety of mechanisms involving the cadherin/catenin complex [38
The results obtained here suggest an enhancement of the potential ability of cancer cells to disperse, a preliminary step in local invasion. A better knowledge of the regulation of the cadherin–catenin system is required for the prevention or treatment of nasopharyngeal carcinoma.
In conclusion, reduced levels of E-cadherin protein in NPC may play an important role in invasion and metastasis. Cytoplasmic β-catenin in NPC leads to impaired cell–cell adhesion, promoting invasive behavior and a metastatic tumor phenotype. Further research is required to clarify the involvement of β-catenin in the mechanism associated with malignant transformation in nasopharyngeal tissues.