Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Biology

Supervisor

Timoshenko, Alexander V.

Abstract

Galectin-12 is a tissue-specific galectin known for governing adipocyte differentiation and the regulation of lipogenesis. This study aimed to evaluate the role of galectin-12 in the differentiation of myeloid and breast cancer cell lines. All-trans retinoic acid (ATRA) and dimethyl sulfoxide (DMSO) were found to differentiate acute myeloid leukemia HL-60 cells into functionally distinct phenotypes of neutrophils which had opposite changes in LGALS12. Neutrophilic differentiation also led to the inhibition of galectin-12 secretion, and an increase in lipid droplet accumulation. Galectin-12 secretion was found to be influenced by a modulator of autophagy, suggesting the involvement of secretory autophagy. Galectin-12 (LGALS12) gene expression and secretion levels were also found to be O-GlcNAc-independent. In breast cancer cell lines, a subtype-specific upregulation of LGALS12 was observed upon ATRA-induced differentiation in triple negative (basal B) MDA-MB-231 cells. These findings point to the role of galectin-12 as a tissue-specific biomarker of cellular differentiation.

Summary for Lay Audience

Cancer cells acquire features of stemness that help them grow uncontrollably or migrate to new sites. This stemness can potentially be reversed through drug treatments by inducing cell differentiation. Galectins are a family of sugar-binding proteins involved in the regulation of cell growth, death and differentiation. Galectin-12 is a tissue-specific galectin that is primarily found in adipocytes where it plays a role in cell differentiation and the regulation of lipid storage. I aimed to examine the role of galectin-12 in cell differentiation using two models, myeloid and breast cancer cell lines. First, I used acute myeloid leukemia HL-60 cells which can be differentiated into neutrophil-like cells using the chemical agents all-trans retinoic acid (ATRA) or dimethyl sulfoxide. Neutrophils are white blood cells that contribute to the immune response against invading pathogens. Galectin-12 was found to have opposite changes in expression upon neutrophilic differentiation with the two agents. This suggests that galectin-12 can be used as a marker to distinguish the two different populations of neutrophils produced. Galectins can also be secreted out of cells where they carry out signaling by binding to sugars on the cell surface. Galectin-12 was found to have its secretion blocked upon the differentiation of HL-60 cells into neutrophils. Four breast cancer cell lines were differentiated into epithelial-like cells with ATRA. An upregulation of galectin-12 gene expression was observed in MDA-MB-231 cells. This suggests that galectin-12 could act as a tumor suppressor gene or marker of select subtypes of breast cancer. Galectins and their activity can also be influenced by a protein modification known as O-GlcNAcylation which is often altered during differentiation. Galectin-12 was found to function in an O-GlcNAc-independent manner in both myeloid and breast cancer cell lines. Together, these findings provide new insight into the role and regulation of galectin-12 in cell differentiation.

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