Hypoxia-inducible Factor 3α1 Increases Epithelial-to-mesenchymal Transition and Iron Uptake to Drive Colorectal Cancer Liver Metastasis

Overview

Journal Br J Cancer

Specialty Oncology

Date 2024 May 1

PMID 38693428

Authors

Luke B Villareal

Daniel M Falcon

Liwei Xie

Xiang Xue

Affiliations

Soon will be listed here.

Abstract

Background/objectives: Hypoxia-inducible factor (HIF)-3α1's role in colorectal cancer (CRC) cells, especially its effects on epithelial-mesenchymal transition (EMT), zinc finger E-box binding homeobox 2 (ZEB2) gene expression, and iron metabolism, remains largely unstudied. This research sought to elucidate these relationships.

Methods: RNA-seq was conducted to investigate the impact of HIF-3α1 overexpression in CRC cells. Dual-luciferase reporter assays assessed the direct targeting of ZEB2 by HIF-3α1. Scratch assays measured changes in cell migration following HIF-3α1 overexpression and ZEB2 knockdown. The effects of HIF-3α1 overexpression on colon tumour growth and liver metastasis were examined in vivo. Iron chelation was used to explore the role of iron metabolism in HIF-3α1-mediated EMT and tumour growth.

Results: HIF-3α1 overexpression induced EMT and upregulated ZEB2 expression, enhancing cancer cell migration. ZEB2 knockdown reduced mesenchymal markers and cell migration. HIF-3α1 promoted colon tumour growth and liver metastasis, increased transferrin receptor (TFRC) expression and cellular iron levels, and downregulated HIF-1α, HIF-2α, and NDRG1. Iron chelation mitigated HIF-3α1-mediated EMT, tumour growth, and survival.

Conclusions: HIF-3α1 plays a critical role in colon cancer progression by promoting EMT, iron accumulation, and metastasis through ZEB2 and TFRC regulation, suggesting potential therapeutic targets in CRC.

Citing Articles

Hypoxia inducible factor 3-alpha promotes a malignant phenotype in colorectal cancer cells.

Lopez-Mejia A, Moreno-Londono A, Fonseca Camarillo G, Yamamoto-Furusho J, Villanueva-Herrero J, de Leon-Rendon J IUBMB Life. 2025; 77(2):e70007.

PMID: 39981666 PMC: 11843525. DOI: 10.1002/iub.70007.

The emerging role of hypoxia and environmental factors in inflammatory bowel disease.

Villareal L, Xue X Toxicol Sci. 2024; 198(2):169-184.

PMID: 38200624 PMC: 10964750. DOI: 10.1093/toxsci/kfae004.

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