Abstract

Pancreatic cancer is currently one of the most difficult diseases to treat due to difficulty of detection and its aggressive nature. In addition, pancreatic cancer has the highest mortality rates compared to other cancer types. These mortality rates are attributable in part to increasing resistance to cancer therapy. Cancer therapy resistance is caused by adaptations that favor cancer cell survival. Some of these adaptations occur intrinsically before chemotherapy exposure (innate resistance) while others are a result of chemotherapy through selective and cellular adaptations (acquired chemoresistance). Important to pancreatic cancer diagnosis and management is to determine an optimal combination of clinical indicators or biomarkers that could detect tumors early with high specificity/sensitivity and with limited invasiveness. In spite of the availability of a plethora of gene products considered as promising pancreatic cancer biomarkers, it is recognized that their combined use with the available clinical information is still insufficient for early diagnosis and for guiding individualized therapeutic interventions and predicting outcomes. The main limitation of the successful use of these biomarkers is that they require invasive procedures such as biopsies. However, there is growing interest in using proteomics approaches to identify tumor-derived serum microvesicles called exosomes and their content, as serological biomarkers. This interest stems from the notion that these blood components are considered “sensors” of molecular events associated with tumorigenesis. One such target that may prove useful in early detection from pancreatic cancer patient serum or plasma is the newly recognized exosomal protein survivin and its alternative splice variants. Survivin, a member of the inhibitor of apoptosis (IAP) family has been linked to chemoresistance among several other hallmarks of cancer. Like many others, this gene undergoes alternative splicing which generates six splice isoforms: survivin WT, ΔEx3, 2β, 3β, 3α and survivin 2α. Although survivin has been linked to chemoresistance, the role of its splice isoforms has not been fully studied. In this thesis we present our results showing the differential expression of survivin splice variants in both acquired and innate chemoresistance and the role that they play in these two types of chemoresistance in pancreatic cancer.

LLU Discipline

Biochemistry

Department

Biochemistry

School

School of Medicine

First Advisor

William H.R. Langridge

Second Advisor

Nathan R. Wall

Third Advisor

Carlos A. Casiano

Fourth Advisor

Maheswari Senthil

Fifth Advisor

Julia Unternaehrer

Degree Name

Doctor of Philosophy (PhD)

Year Degree Awarded

2021

Date (Title Page)

5-2021

Language

English

Library of Congress/MESH Subject Headings

Survivin; Drug Resistance, Neoplasm; RNA Splicing; Carcinoma, Pancreatic Ductal

Type

Dissertation

Page Count

xviii, 149 p.

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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