Cadherin Gene Overexpression Linked to WNT Signaling in Nasopharyngeal Carcinoma Cells

Cadherin genes, which encode the calcium-dependent adhesion molecules that hold epithelial tissues together, are consistently switched to high levels in nasopharyngeal carcinoma (NPC), and silencing them in laboratory-grown tumor cells slows proliferation, colony formation, and migration. That is the central finding of a new open-access study published in the journal Cell Division, in which researchers combined cell culture experiments with a battery of public cancer databases to probe the roles of CDH1, CDH2, and CDH3 in this aggressive malignancy. The work also points to a possible connection with WNT signaling, one of the most frequently dysregulated pathways in human cancer, although the authors themselves caution that this mechanistic link remains a hypothesis rather than a demonstrated causal pathway.

Nasopharyngeal carcinoma arises from the epithelial lining of the nasopharynx, the region where the nasal cavity meets the throat. It is uncommon worldwide but markedly more frequent in Southeast Asia, particularly southern China, where it ranks among the leading causes of cancer-related death. Its development is attributed to a combination of genetic susceptibility, Epstein-Barr virus infection, and environmental factors including tobacco smoke exposure, certain dietary habits, and chronic consumption of salted fish and preserved foods. Even with radiation therapy, chemotherapy, and targeted treatments available, patients often face poor outcomes because the disease tends to be diagnosed late and spreads readily to regional lymph nodes and distant organs. The molecular mechanisms behind this aggressiveness and treatment resistance remain incompletely understood, motivating the search for new biomarkers and drug targets.

The research team, led by Wenfeng Yao and Guangke Wang, began with expression measurements. They cultured eight normal nasal or nasopharyngeal epithelial cell models and six NPC cell lines, then used RT-qPCR to quantify the three cadherin genes. All three were significantly upregulated in the cancer cell lines compared with the normal controls, with p values below 0.001. Receiver operating characteristic analysis, built on this cell-line data, showed strong discriminatory performance: area under the curve values of 0.95 for CDH1, 0.92 for CDH2, and 0.93 for CDH3, with corresponding sensitivity and specificity values in the high 0.80s and low 0.90s. The authors are explicit that these figures reflect the ability to distinguish cancer cells from normal cells under experimental conditions, and that independent patient cohorts and prospective clinical samples would be required to establish real diagnostic utility.

To check whether the overexpression pattern extends beyond their own cultures, the team turned to the GSCA and Human Protein Atlas databases. Gene expression analysis of head and neck squamous cell carcinoma or NPC tumor tissues versus normal tissues confirmed significant upregulation of all three genes, with false discovery rate values of 6.2e-10 for CDH1, 3.2e-02 for CDH2, and 7.3e-08 for CDH3. Immunohistochemistry images from the Human Protein Atlas showed high protein-level staining for the three cadherins in tumor samples. Expression across pathological stages varied, with CDH1 and CDH2 appearing more strongly expressed in later stages III and IV, a pattern the authors interpret as consistent with a role in tumor progression. Gene set enrichment analysis further associated cadherin expression with gene sets linked to cancer progression.

The team also examined the epigenetic and genetic landscape of these genes. Promoter methylation analysis using the OncoDB database revealed significant hypomethylation of CDH1, CDH2, and CDH3 in tumor samples compared with normal tissues, and correlation analysis in GSCA showed negative relationships between methylation and expression: weak for CDH1 (r = −0.17), stronger for CDH2 (r = −0.33), and moderate for CDH3 (r = −0.27), all statistically significant. This fits the idea that reduced promoter methylation helps drive the elevated expression seen in tumors. Notably, however, survival analysis based on methylation levels showed no significant association with overall survival, suggesting that methylation status alone does not carry prognostic information in this dataset.

Mutation and copy number analysis through cBioPortal added another layer. In the analyzed head and neck squamous cell carcinoma or NPC samples, CDH3 showed the highest mutation rate at 44 percent, followed by CDH2 at 33 percent and CDH1 at 22 percent, with most mutations being missense changes, followed by nonsense mutations and in-frame deletions. Somatic mutation rates per gene were 0.79 percent for CDH1, 1.18 percent for CDH2, and 1.57 percent for CDH3. Copy number variation analysis revealed amplifications in all three gene regions, with CDH1 and CDH3 showing heterogeneous amplifications and CDH2 displaying a mixture of heterozygous and homozygous gains. Together, these alterations indicate that both sequence mutations and gene dosage changes may contribute to cadherin dysregulation.

Prognostic findings were more nuanced than the headline association suggests. Using the KM Plotter database, higher expression of all three genes was associated with poorer overall survival, but the confidence intervals for CDH1 (hazard ratio 1.18, 95 percent CI 0.87–1.59) and CDH2 (hazard ratio 1.26, 95 percent CI 0.95–1.67) crossed 1.0, meaning these associations did not reach significance in the Cox proportional hazards model and should be read as trends. Only CDH3 showed a statistically robust association, with a hazard ratio of 1.39 (95 percent CI 1.06–1.82, log-rank p = 0.015). Analysis in the cSurvival database showed clearer survival curve separation for CDH3, while CDH1 and CDH2 displayed overlapping confidence bands. The authors therefore position CDH3 as the strongest candidate prognostic biomarker among the three.

The most direct evidence came from loss-of-function experiments. Using siRNA to knock down CDH1, CDH2, or CDH3 individually in the NPC cell lines 5–8 F and C666-1, the researchers confirmed reduced mRNA and protein expression, then measured functional consequences. Knockdown of any of the three genes significantly reduced cell proliferation, produced fewer and smaller colonies in clonogenic assays, and impaired wound closure in migration assays, all with p values below 0.01. These in vitro results support the idea that cadherin genes actively promote growth and motility programs in NPC cells, though the authors stress that cell culture cannot recapitulate the tumor microenvironment, immune modulation, or systemic factors of a living organism, and no in vivo validation was performed.

The WNT connection emerged from two converging but indirect lines of evidence. Correlation analysis using GEPIA2 showed that cadherin gene expression was positively associated with expression of WNT pathway components: CDH1 correlated with AXIN1 (R = 0.23) and WNT3A (R = 0.62), CDH2 with AXIN1 (R = 0.36) and WNT3A (R = 0.62), and CDH3 modestly with WNT3A (R = 0.30) but not significantly with AXIN1. When the team silenced the cadherin genes in NPC cells, RT-qPCR showed increased expression of both AXIN1, a negative regulator of canonical WNT signaling, and WNT3A, a WNT ligand. The authors interpret this as a possible alteration of pathway dynamics rather than proof of activation or suppression, and they note that assays such as β-catenin nuclear localization analysis and TOP/FOP luciferase reporter experiments would be needed to test whether cadherins directly modulate canonical WNT activity. Their proposed model, in which cadherin upregulation enhances WNT3A signaling and β-catenin-driven transcription, remains explicitly speculative.

Additional database analyses rounded out the picture. TISIDB-based correlations linked cadherin expression to reduced levels of immune inhibitors such as TGFβ1 and LGALS3, and immune infiltration analysis showed negative correlations with certain immune cell populations, findings the authors suggest could relate to immune evasion, though the mechanisms remain unclear. Drug sensitivity analysis associated high cadherin expression with resistance to chemotherapy agents including bortezomib, cisplatin, and paclitaxel. Protein interaction and enrichment analyses connected the cadherins to adherens junction components and to WNT-related biological processes. The study has clear limitations the authors acknowledge: all functional work was confined to cell lines, the mechanistic WNT model lacks direct functional evidence, no longitudinal patient data beyond survival database analyses were available, and residual batch effects across the public datasets used cannot be excluded. Within those boundaries, the work lays groundwork for cadherin genes, particularly CDH3, as candidates for future diagnostic and therapeutic research in nasopharyngeal carcinoma.

Subject of Research: Cadherin gene dysregulation, WNT signaling correlation, and functional knockdown experiments in nasopharyngeal carcinoma cell lines and public cancer databases

Article Title: Role of cadherin gene dysregulation in WNT signaling and nasopharyngeal carcinoma

Article References: Yao, W., Qin, L., Li, Q., Sun, Z., & Wang, G. (2026). Role of cadherin gene dysregulation in WNT signaling and nasopharyngeal carcinoma. Cell Division, 21(1), Article 11. https://doi.org/10.1186/s13008-026-00187-z

Image Credits: AI Generated

DOI: 10.1186/s13008-026-00187-z

Keywords: nasopharyngeal carcinoma, cadherin genes, CDH1, CDH2, CDH3, WNT signaling, gene knockdown, siRNA, biomarkers, copy number variation, promoter methylation, cell migration