Hypoxia-inducible factor 3α1 increases epithelial-to-mesenchymal transition and iron uptake to drive colorectal cancer liver metastasis
Menée à l'aide de lignées cellulaires et de modèles murins de cancer colorectal, cette étude met en évidence un mécanisme par lequel le facteur 3 alpha 1 inductible par l'hypoxie, en augmentant la transition épithélio-mésenchymateuse et l'absorption du fer, favorise le développement de métastases hépatiques
Background/objectives: Hypoxia-inducible factor (HIF)-3
α1’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
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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
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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
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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.