Epithelial cadherins with catenins form the E-cadherin-catenin complex that acts on cell-to-cell adhesion. The loss of these complex lead to the reduction or absence of epithelial cadherin expression in the cell membrane, cytoplasmic accumulation of β-catenin and its translocation to the nucleus, contributing to carcinogenic events. The objective of this study was to evaluate the expression of epithelial cadherin and β-catenin in patients with laryngeal tumor. A retrospective study of 52 patients with glottic or supraglottic squamous cell carcinoma was conducted and evaluated according to the tumor site, histological differentiation, TNM stage, survival analysis and compared with the immunohistochemical expression of epithelial cadherin and β-catenin. We observed statistically significant association between the epithelial cadherin expression reduction and supraglottic localization of the lesion, the presence of cervical metastasis, poorly differentiated tumors and locally advanced tumors when in glottic topography. Related to the expression of β-catenin, statistical significance was also found to the presence of cervical metastasis and tumor of low differentiation with the decreased expression of this marker. Regarding survival analysis, the low expression of β-catenin is related to worse overall survival and the reduction of expression of both markers to worse disease-free survival. We concluded that the reduction in expression of the markers studied leads to a prognostic impact as they are related to tumors with greater local aggressiveness and presence of cervical metastasis.

Tumor cells acquire metastasis-associated (MA) phenotypes following genetic alterations in them which cause deregulation of different signaling pathways. Earlier, we reported that an upregulation of the Wnt-beta-catenin pathway (WP) is one of the genetic salient features of triple-negative breast cancer (TNBC), and WP signaling is associated with metastasis in TNBC. Using cBioPortal, here we found that collective % of alteration(s) in WP genes, CTNNB1, APC and DVL1 among breast-invasive-carcinomas was 21% as compared to 56% in PAM50 Basal. To understand the functional relevance of WP in the biology of heterogeneous/metastasizing TNBC cells, we undertook this comprehensive study using 15 cell lines in which we examined the role of WP in the context of integrin-dependent MA-phenotypes. Directional movement of tumor cells was observed by confocal immunofluorescence microscopy and quantitative confocal-video-microscopy while matrigel-invasion was studied by MMP7-specific casein-zymography. WntC59, XAV939, sulindac sulfide and beta-catenin siRNA (1) inhibited fibronectin-directed migration, (2) decreased podia-parameters and motility-descriptors, (3) altered filamentous-actin, (4) decreased matrigel-invasion and (5) inhibited cell proliferation as well as 3D clonogenic growth. Sulindac sulfide and beta-catenin siRNA decreased beta-catenin/active-beta-catenin and MMP7. LWnt3ACM-stimulated proliferation, clonogenicity, fibronectin-directed migration and matrigel-invasion were perturbed by WP-modulators, sulindac sulfide and GDC-0941. We studied a direct involvement of WP in metastasis by stimulating brain-metastasis-specific MDA-MB231BR cells to demonstrate that LWnt3ACM-stimulated proliferation, clonogenicity and migration were blocked following sulindac sulfide, GDC-0941 and beta-catenin knockdown. We present the first evidence showing a direct functional relationship between WP activation and integrin-dependent MA-phenotypes. By proving the functional relationship between WP activation and MA-phenotypes, our data mechanistically explains (1) why different components of WP are upregulated in TNBC, (2) how WP activation is associated with metastasis and (3) how integrin-dependent MA-phenotypes can be regulated by mitigating the WP.