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CD44v6 Is Associated with Tumor Aggressiveness and Chemoresistance in Bladder Cancer

ABSTRACT: Bladder cancer represents a significant clinical and public health challenge. This malignancy is characterized by a very high propensity for recurrence and progression, underscoring the critical need for novel biomarkers to enhance early detection, prognosis, and specific therapeutic strategies. In the quest for such biomarkers, the CD44 family, particularly its variant isoform CD44v6, has emerged as a molecule of interest due to its pivotal roles in tumorigenesis and cell migration. Here we present a comprehensive study that elucidates the expression patterns and functional significance of CD44 and CD44v6 in bladder cancer. Utilizing robust methodological frameworks that include gene expression analyses, immunohistochemistry for protein localization, and a series of in vitro and in vivo functional assays, we systematically investigate the roles of these glycoproteins in bladder cancer pathology. Our analysis demonstrates a strong association between either elevated CD44 or CD44v6 expression and adverse clinical outcomes. Functional investigations attribute enhanced proliferative, migratory, and invasive capacities of bladder cancer cells to CD44v6 expression, indicating its contributory role in tumor aggressiveness and, importantly, in resistance to cisplatin treatment. In summary, our study places CD44 and CD44v6 as key biomarkers and putative therapeutic targets in bladder cancer. By shedding light on their mechanistic roles in cancer progression, we pave the way for the development of targeted therapeutic strategies that could potentially improve patient management and outcomes in bladder cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276545 | GEO | 2026/02/18

REPOSITORIES: GEO

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Project description:This project was done in collaboration with Dr. Richard Cummings to examine sialylation of CD44v6 and its role in clearance of neutrophils from inflamed intestinal epithelium. Specifically, we have employed a functional approach using membrane preparations from interferon gamma-stimulated intestinal epithelial cells to generate a monoclonal antibody, designated GM35, which blocks neutrophil transepithelial migration through the promotion of neutrophil adhesion at the apical surface of the intestinal epithelium. Protein biochemistry, sequencing, confocal microscopic analysis, and immunoprecipitation studies all identify the protein ligand for this antibody as CD44v6. However, selective inhibition of O- or N-linked glycosylation reveal that the antibody is specific for an O-linked glycotope and glycoarray analysis of the GM35 antibody by Core H of the Consortium for Functional Glycomics reveal that this antibody binds with high affinity and specificity to a carbohydrate epitope consistent in structure with sLeA. Inhibition of O-linked glycosylation attenuated both GM35 binding and its functional effects as did specific cleavage of sialic acid residues from the cell surface, using neuraminidase, although the functional effects of cleavage were smaller and harder to assess. CD44v6 has previously been studied as a marker of inflammation in Inflammatory Bowel Disease, and GM35 staining is clearly upregulated by interferon gamma in T84 and HT29 intestinal epithelial cells. The specific enzymes governing the sialylation of CD44v6 in intestinal epithelium have yet to be determined. Analysis of a panel of intestinal epithelial cells including T84, HT29, and Caco-2 cells revealed that cell-type specific regulation of both splicing and glycosylation is essential for the regulation of the expression of the GM35 epitope. And, forcible expression of CD44 in Caco-2 cells, which are negative for CD44v6 at baseline, results only in upregulation of previously expressed isoforms of CD44, but not in GM35 expression. Based on western blot and immunofluorescent staining, GM35 expression is greatest in interferon gamma-treated T84 cells. Thus, we analyzed RNA samples for the expression of glycosylation specific genes in interferon gamma-stimulated T84 cells relative to that of both non-stimulated T84 cells and GM35-negative Caco-2 cells in order to identify glycosylation-specific targets contributing to the interferon gamma-dependent upregulation of sialylated CD44v6 in intestinal epithelial cells.

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CD44v6 Is Associated with Tumor Aggressiveness and Chemoresistance in Bladder Cancer

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