Clinical and functional role of CD44 in gastric cancer

• Autor(a) principal: Eiras, Mariana Gonçalves
• Data de Publicação: 2023
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/40549
• topic: Gastric cancer; CD44; Glycosylation; SLeᵃ

Gastric cancer (GC) poses a significant challenge in the field of oncology, characterized by delayed detection and limited treatment efficacy in advanced stages. The glycoprotein CD44 has been implicated in the progression of GC, with its altered expression and aberrant glycosylation patterns contributing to the disease’s pathogenesis and aggressiveness. However, the role and clinical significance of CD44 in GC remain controversial, possibly attributable to the extensive alternative splicing and glycosylation processes that generate a myriad of distinct functional isoforms. This study seeks to provide novel insights into the clinical and functional role of glycosylated CD44 in GC. A library of 187 gastric tumours was screened for CD44, STn and SLeᵃ antigens expression by immunohistochemistry, aiming to identify potential correlations with various clinicopathological variables. The co-localization of CD44 and SLeᵃ was assessed through PLA. RT-PCR assay was used to determine the CD44 isoform expression in GC cell lines and FFPE tumour tissues. In vitro siRNA experiments to silence CD44 were conducted to delve into its potential functional role in cell proliferation and migration. Immunohistochemical staining revealed that CD44 antigen expression was evident in 35% of cases, and this expression did not exhibit a significant correlation with a poorer prognosis. However, when SLeᵃ was co-expressed, it significantly affected patient's prognosis, being associated with distant metastasis and advanced clinical stages. In turn, co-expression with STn did not revealed statistically significant correlations with any clinicopathological variable. Transcriptomic analysis unveiled differential expression levels of CD44 isoforms in GC cell lines, however, no differences were observed in the MSI subtype of tumours. Furthermore, CD44 silencing demonstrated a noteworthy impact on cell proliferation, while it did not elicit effects on cell migration. Overall, this study highlights the potential of CD44-SLeᵃ glycoform as a cancer-specific signature that holds promise for novel targeted therapeutics. Future research should focus on disclosing CD44 splicing glycocode in GC through a glycoproteogenomics approach, and thus narrowing down CD44 isoforms to its clinically relevant glycoepitopes may provide key molecular insights for highly specific GC targeting therapies.