All ETDs from UAB

Advisory Committee Chair

Upender Manne

Advisory Committee Members

William E Grizzle

Sejong Bae

Donald Buchsbaum

Xu Feng

Boris Pasche

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Colorectal cancer (CRC) is a heterogeneous disease, and factors such as tumor location, the environment, genetics, and ethnic differences, can influence its development and progression. Over the last few decades, overall CRC mortality rates have declined; however, racial disparities in mortality rates have increased. The discovery of biomarkers that focus on identifying individual differences based on confounders such as tumor stage and patient race/ethnicity is needed, for such biomarkers can lead to development of personalized therapeutic approaches to target these molecules. MicroRNAs (miRNAs) are a class of small molecules that regulate genes at the post-transcriptional level. Altered miRNA expression levels are found in many human malignancies, including CRCs, and aberrant expression of miRNAs is associated with tumor initiation and cancer progression. Previous studies have highlighted the value of miRNA expression profiles in the prognosis and therapeutic outcome of patients with CRC; however, their value based on the patient race/ethnicity and pathologic stage is not yet determined. Therefore, the goals of this study are to evaluate the prognostic value of a panel of miRNAs in African American (Black) and non-Hispanic Caucasian (White) CRC patients and to identify the oncogenic targets of clinically relevant miRNAs. In this dissertation, we show that the prognostic value of miRNAs in CRCs varies with patient race/ethnicity and pathologic stage of disease. We also show that some miRNAs are more highly expressed in Black CRC patients than in White CRC patients and that they specifically affect the outcome for Black patients. We established that, of these miRNAs, miR-181b is an independent prognostic marker for Stage III CRCs of Black patients. Furthermore, we found that miR-181b targets integrin &alpha3; and Bim, which are involved in cell signaling pathways that promote cell proliferation, cell growth, inhibit apoptosis, and thereby promote CRC progression. Furthermore, these findings have clinical implications in identifying aggressive phenotypes of CRCs and in identifying high-risk patients, thus maximizing the benefits of adjuvant therapy. These findings suggest that, in CRCs, miR-181b is a target for new therapeutics.

Share

COinS