Biomedical Sciences ETDs
Publication Date
Winter 12-12-2024
Abstract
The interplay between hypoxia and iron metabolism drives colorectal cancer (CRC) progression. This dissertation investigates hypoxia-inducible factor 3α1 (HIF-3α1), a protein linked to poor CRC outcomes, focusing on its roles in metastasis, epithelial-to-mesenchymal transition (EMT), and iron loading via transferrin receptor (TFRC). HIF-3α1 promotes CRC cell migration by upregulating zinc finger E-box binding homeobox 2 (ZEB2) and suppressing N-myc downstream-regulated gene 1 (NDRG1), while TFRC-mediated iron accumulation supports tumor growth and survival. Iron chelation reduced EMT markers, migration, and tumor growth, highlighting iron's critical role. Additionally, HIF-3α1-induced TFRC expression altered nucleotide synthesis enzymes carbamoyl-phosphate synthetase-aspartate transcarbamoylase-dihydroorotase (CAD) and phosphoribosyl pyrophosphate amidotransferase (PPAT), fueling cancer proliferation. Repurposed drugs targeting nucleotide synthesis reduced tumor growth in an iron-dependent manner. These findings suggest combining HIF-3α1 inhibition and iron chelation as a promising therapeutic approach to suppress CRC metastasis and improve patient outcomes.
Keywords
Cancer, Hypoxia, Iron, EMT, Nucleotide synthesis, Metastasis
Document Type
Dissertation
Language
English
Degree Name
Biomedical Sciences
Level of Degree
Doctoral
Department Name
Biomedical Sciences Graduate Program
First Committee Member (Chair)
Laurie Hudson
Second Committee Member
Laura Gonzalez-Bosc
Third Committee Member
Matthew Campen
Fourth Committee Member
Xiang Xue
Recommended Citation
Villareal, Luke. "HYPOXIA-INDUCIBLE FACTOR 3a1'S ROLE IN PROMOTING IRON LOADING, TUMORIGENESIS, AND METASTASIS IN COLORECTAL CANCER." (2024). https://digitalrepository.unm.edu/biom_etds/273
