DOI
https://doi.org/10.25772/XDA7-Q049
Defense Date
2023
Document Type
Thesis
Degree Name
Doctor of Philosophy
Department
Clinical and Translational Sciences
First Advisor
Dr. Paul Fisher
Second Advisor
Dr. Swadesh Das
Third Advisor
Dr. Steven Grant
Fourth Advisor
Dr. Jiong Li
Fifth Advisor
Dr. Xiang-Yang Wang
Abstract
Malignant melanoma (MM) is the most aggressive skin cancer and the most frequent skin disorder in Caucasians. MM is associated with aggressive and progressive disease states, leading to major cancer-related morbidity and mortality. Recent investigations identify an alternative pathway -vasculogenic mimicry (VM), which is considered a cancer hallmark that can independently facilitate tumor neovascularization by the formation of fluid-conducting and vascular endothelial cells. MM cells undergoing VM can dedifferentiate into numerous cellular phenotypes and acquire endothelial-like features, resulting in the formation of the de novo matrix-rich vascular-like networks, such as plasma and red blood cells. The co-generation of endothelial cells, channels, laminar structures, and heparin sulfate proteoglycans are the main pathophysiological characteristics of VM in human melanoma patients. In highly aggressive melanoma cells downregulation of vascular endothelial cadherin and upregulation of ECM components promote the perfusion of the VM pathway. We investigated whether mda-9/syntenin/syndecan binding protein, a pro-metastatic gene, affects VM in MM. The expression of mda-9/syntenin was modulated using gain-of-function and loss-of-function strategies to determine its potential role in VM. Downregulation of mda-9/syntenin in aggressive melanoma cells decreases VM, while over expressing mda-9/syntenin in immortalized melanoma cells increases VM. Also, we found that miR-210 a potential downstream target of mda-9 associated with hypoxia showed a rescue effect when overexpression of miR-210 and downregulation of mda-9 was examined in aggressive melanoma cells in VM. These findings shed light on a novel role and molecular mechanism of action of mda-9/syntenin in VM via exploring the pathways associated with inclusion of miRNA (miR-210), which may contribute significantly to the metastatic phenotype of these aggressive cancers.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-12-2023
Included in
Medical Cell Biology Commons, Medical Genetics Commons, Translational Medical Research Commons