Hypoxia-Inducible Factor 3α1's Role in Promoting Iron Loading, Tumorigenesis, and Metastasis in Colorectal Cancer

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.