Graduation Date

Spring 5-4-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Joyce C Solheim

Abstract

Human leukocyte antigen (HLA) class I molecules are composed of a light chain (beta 2-microglobulin (β2m)) and HLA heavy chain. The heavy chains of these molecules have three different isotypes (–A, -B, and –C) and are highly polymorphic with thousands of sequence variations termed allotypes. The best-known role for these molecules is within the immune system, however, recent research implicates components of this molecule can function outside of this known immune role by contributing to cell migration. However, no studies have been published thus far investigating this non-immune function in pancreatic cancer. Therefore, I examined the role of HLA class I molecule components in pancreatic cancer cell migration.

My studies showed that when β2m was knocked down using β2m-specific siRNA, cell migration decreased in the S2-013 and PANC-1 cells but increased in the MIA PaCa-2 cells. Interactions with amyloid precursor-like protein 2 (APLP2) as well as total APLP2 protein expression are potential mediators of these effects. HLA-B knockdown using HLA-B-specific siRNA increased cell migration in S2-013 cells, while in both the PANC-1 and MIA PaCa-2 cells knockdown decreased migration. Alterations in integrin beta 1 (ITGB1) and focal adhesion kinase (FAK) are potential intermediates in HLA-B’s effects on cell migration. Furthermore, knockdown using allotype-specific siRNA of HLA-A24 in the S2-013 cell line and HLA-A2 in PANC-1 cell line increased migration while knockdown of HLA-A2 in the S2-013 cell line and HLA-A24 in the MIA PaCa-2 cell line reduced cell migration. Mechanistically, APLP2 C-terminal fragment (APLP2-CT) and epidermal growth factor receptor (EGFR) are likely mediators of this phenotype. Finally, the histone deacetylase (HDAC) inhibitor M344 and its effects on APLP2 processing in the S2-013 pancreatic cancer cell line was interrogated as previous studies indicated M344 treatment reduced levels of β-site APP cleaving enzyme 1 (BACE1), a proteolytic enzyme involved in APLP2 cleavage. M344 treatment of S2-013 cells led to a significant reduction in cell proliferation, migration, and APLP2-CT expression. Overall, this work sheds light on a novel role for the HLA class I molecules in pancreatic cancer outside of their known immune function and implicates M344 as a potential new therapeutic for this lethal disease.

Available for download on Sunday, April 18, 2021

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