Effect of MUC1/β-catenin interaction on the tumorigenic capacity of pancreatic CD133+ cells

Abstract

Despite the fact that the biological function of cluster of differentiation (CD)133 remains unclear, this glycoprotein is currently used in the identification and isolation of tumor-initiating cells from certain malignant tumors, including pancreatic cancer. In the present study, the involvement of mucin 1 (MUC1) in the signaling pathways of a highly tumorigenic CD133+ cellular subpopulation sorted from the pancreatic cancer cell line HPAF-II was evaluated. The expression of MUC1-cytoplasmic domain (MUC1-CD) and oncogenic signaling transducers (epidermal growth factor receptor, protein kinase C delta, glycogen synthase kinase 3 beta and growth factor receptor-bound protein 2), as well as the association between MUC1 and β-catenin, were characterized in HPAF-II CD133+ and CD133low cell subpopulations and in tumor xenografts generated from these cells. Compared with HPAF CD133low cells, HPAF-II CD133+ cancer cells exhibited increased tumorigenic potential in immunocompromised mice, which was associated with overexpression of MUC1 and with the accordingly altered expression profile of MUC1-associated signaling partners. Additionally, MUC1-CD/β-catenin interactions were increased both in the HPAF-II CD133+ cell subpopulation and derived tumor xenografts compared with HPAF CD133low cells. These results suggest that, in comparison with HPAF CD133low cells, CD133+ cells exhibit higher expression of MUC1, which contributes to their tumorigenic phenotype through increased interaction between MUC1-CD and β-catenin, which in turn modulates oncogenic signaling cascades.

MUC1: Structure, Function, and Clinic Application in Epithelial Cancers

“…The MUC1 N-terminus, which is extracellular, contains highly conserved VNTR of 20 amino acids (HGVTSAPDTRPAPGSTAPPA), which are rich in proline (Pro or P), threonine (Thr or T), and serine (Ser or S) residues. The N-terminus are extensively modified by O -linked glycans (Ser and Thr residues) [ 5 , 8 , 29 , 31 , 32 ]. Notably, MUC1-N is the mucin component of the heterodimer that functions as a cell barrier, blocking cell-cell and cell-extracellular matrix interactions and protecting cells from cellular and pathogenic invasions while keeping the epithelium moist and repairing it [ 33 ].…”

“…Overall, MUC1 affects a variety of tumor progression pathways. Pancreatic CD133 + cells exhibit higher expression levels of MUC1, contributing to their tumorigenic phenotype through increased interactions between MUC1-C and β-catenin, which in turn modulate oncogenic signaling cascades [ 31 ]. In HCC cells, MUC1 overexpression promotes HCC progression and tumorigenesis through the JNK/TGF-β signaling pathway [ 74 ].…”

The polypeptide GALNT6 Displays Redundant Functions upon Suppression of its Closest Homolog GALNT3 in Mediating Aberrant O-Glycosylation, Associated with Ovarian Cancer Progression

“…The downregulation of the MUC1 protein, observed in our study upon knocking down both the GALNT3 and GALNT6 genes, emphasizes its possible role in enhancing the malignant phenotype of ovarian cancer. The exact pathway of how MUC1 contributes to many cancer malignant phenotypes has not been clearly identified; however, there are several studies that link MUC1 in inducing major antiapoptotic pathways [30,31], in addition to other studies that confirm MUC1 interaction with canonical pathways associated with cellular transformation and cell growth [32,33]. Thus, our study emphasizes GALNT3 and GALNT6 as druggable EOC targets, since they show potential importance in targeting MUC1 protein expression.…”

Renal Cl-/H+ antiporter ClC-5 regulates collagen production and release in Dent Disease models

“…ClC-5 deletion activates β-catenin pathway E-cadherin can form a complex with β-catenin, and its loss can promote β-catenin release from PM and translocation to the nucleus, facilitating epithelial-mesenchymal transition (EMT), promoting collagen transcription and leading to renal fibrosis (26)(27)(28). Furthermore, β-catenin can also bind to MUC1 (29). Thus, since ClC-5 deletion reduces both Ecadherin/MUC1 levels, we tested β-catenin localization.…”