Document Type

Dissertation - Open Access

Award Date

2024

Degree Name

Doctor of Philosophy (PhD)

Department / School

Chemistry and Biochemistry

First Advisor

Rachel Willand Charnley

Abstract

Hypersialylation is a prognostic biomarker in cancer cells. The upregulated sialic acid expression on cancer cells facilitates tumorigenesis by playing a critical role in cancer cell proliferation and growth, immune evasion, cell signaling, and metastasis by interacting with various carbohydrate-binding molecules. Sialic acids on cancer cell surface undergo various modifications like O-acetylation at positions 4,7,9 de-acetylation and addition of glycolyl group at position 5. In our first chapter we analyzed the effect of de-acetylated sialic acid on migration via selectin binding in colon cancer cell line HCT116 and in lung cancer cell line A549. Selectins are calcium-dependent cell adhesion molecules that mediate cellular adhesion in cancer to facilitate metastasis. We have shown increased binding of E, P, and L selectin on de-acetylated sialic acid on colon and lung cancer cell lines HCT116 and A549. Deacetylated sialic acid expression on the cell surface also enhances migration in colon and lung cancer cells HCT116 and A549. Our second project is based on previous studies that Sushi domain-containing protein 2 (SUSD2) is an N-linked type 1 transmembrane glycoprotein that is upregulated in breast cancer cells with little or no expression in normal breast tissues. Previous studies reported cell surface expression of SUSD2 promoted immune evasion and invasion in breast cancer cells and correlated with cell surface detection of Galectin-1. The presence of Galectin-1 on the cancer cell surface is an established mediator of tumorigenesis. Here we focused on analyzing if sugar molecules carried by N-linked glycosylation on SUSD2 have any role in binding Galectin-1 and to promote immune evasion and invasion in MDA-MB-231 and SKBR3 breast cancer cell lines. We identified the sugar molecules carried by SUSD2 and determined the role of major terminal sugar molecules to bind Galectin-1. We found that sialic acid, de-acetylated sialic acid, and β-galactose on LacNAc on SUSD2 are required to bind Galectin-1 to SUSD2 on breast cancer cell surface. We have shown that SUSD2 enhances immune inhibitory siglec ligand interaction to facilitate immune evasion in breast cancer. We have also shown glycosylated SUSD2 enhances E, P, and L selectin binding to facilitate migration in MDA-MB-231 and SKBR3.

Publisher

South Dakota State University

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Rights Statement

In Copyright