Abstract
P120-catenin (p120ctn) exerts important roles in regulating E-cadherin and invasiveness in cancer cells. However, the mechanisms by which p120ctn isoforms 1 and 3 modulate E-cadherin expression are poorly understood. In the current study, HBE, H460, SPC and LTE cell lines were used to examine the effects of p120ctn isoforms 1A and 3A on E-cadherin expression and cell invasiveness. E-cadherin was localized on the cell membrane of HBE and H460 cells, while it was confined to the cytoplasm in SPC and LTE cells. Depletion of endogenous p120ctn resulted in reduced E-cadherin expression; however, p120ctn ablation showed opposite effects on invasiveness in the cell lines by decreasing invasiveness in SPC and LTE cells and increasing it in HBE and H460 cells. Restitution of 120ctn isoform 1A restored E-cadherin on the cell membrane and blocked cell invasiveness in H460 and HBE cells, while it restored cytoplasmic E-cadherin and enhanced cell invasiveness in SPC and LTE cells. P120ctn isoform 3A increased the invasiveness in all four cell lines despite the lack of effect on E-cadherin expression, suggesting a regulatory pathway independent of E-cadherin. Moreover, five p120ctn isoform 1A deletion mutants were constructed and expressed in H460 and SPC cells. The results showed that only the M4 mutant, which contains N-terminal 1–54 amino acids and the Armadillo repeat domain, was functional in regulating E-cadherin and cell invasiveness, as observed in p120ctn isoform 1A. In conclusion, the N-terminal 1–54 amino acid sequence and Armadillo repeat domain of p120ctn isoform 1A are indispensable for regulating E-cadherin protein. P120ctn isoform 1A exerts opposing effects on cell invasiveness, corresponding to the subcellular localization of E-cadherin.
Highlights
To date, a number of regulatory mechanisms have been discovered involving carcinogenesis and tumor progression
When cells were grown under conventional culture conditions, expression of E-cadherin and p120ctn were restricted to the cell membrane in human bronchial epithelial cell line (HBE) and H460 cells
Consistent with previous studies [11,15,16,17], we found that ablation of endogenous p120ctn resulted in noticeably decreased E-cadherin expression, to the extent that the immunofluorescence signal was hardly detected in all four cell lines adopted in this study, suggesting that p120ctn exerts an important role in Ecadherin stability [12]
Summary
A number of regulatory mechanisms have been discovered involving carcinogenesis and tumor progression. Among these, increased experimental evidence has demonstrated that cadherin-mediated cell-cell interaction plays a pivotal role in the development and progression of many tumors [1,2]. In many human cancers, reduced or abnormal expression of E-cadherin results in loss of cell-cell adhesion, which correlates with increased neoplastic cell proliferation, invasiveness and metastasis [5,6,7,8]. P120-catenin (p120ctn), a member of the catenin family, can interact directly with the intracellular domain of E-cadherin, and plays important roles in regulating cell-cell adhesion [9,10,11,12,13]. Down-regulation, or delocalization of p120ctn results in loss of E-cadherin and correlates with the progression of several human tumors [10,11,15,16,17]. Recent studies have suggested that p120ctn may have a function on tumor in two opposing directions by either promoting or suppressing tumor growth and invasiveness, depending on whether or not E-cadherin is expressed [18,19]
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