Hypoxia-inducible factor 3α1 increases epithelial-to-mesenchymal transition and iron uptake to drive colorectal cancer liver metastasis.

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.

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

Inflammatory bowel disease (IBD) is a chronic and debilitating disorder characterized by inflammation of the gastrointestinal tract. Despite extensive research, the exact cause of IBD remains unknown, hampering the development of effective therapies. However, emerging evidence suggests that hypoxia, a condition resulting from inadequate oxygen supply, plays a crucial role in intestinal inflammation and tissue damage in IBD. Hypoxia-inducible factors (HIFs), transcription factors that regulate the cellular response to low oxygen levels, have gained attention for their involvement in modulating inflammatory processes and maintaining tissue homeostasis. The two most studied HIFs, HIF-1α and HIF-2α, have been implicated in the development and progression of IBD. Toxicological factors encompass a wide range of environmental and endogenous agents, including dietary components, microbial metabolites, and pollutants. These factors can profoundly influence the hypoxic microenvironment within the gut, thereby exacerbating the course of IBD and fostering the progression of colitis-associated colorectal cancer. This review explores the regulation of hypoxia signaling at the molecular, microenvironmental, and environmental levels, investigating the intricate interplay between toxicological factors and hypoxic signaling in the context of IBD, focusing on its most concerning outcomes: intestinal fibrosis and colorectal cancer.

Transferrin Receptor-Mediated Iron Uptake Promotes Colon Tumorigenesis.

Transferrin receptor (TFRC) is the major mediator for iron entry into a cell. Under excessive iron conditions, TFRC is expected to be reduced to lower iron uptake and toxicity. However, the mechanism whereby TFRC expression is maintained at high levels in iron-enriched cancer cells and the contribution of TFRC to cancer development are enigmatic. Here the work shows TFRC is induced by adenomatous polyposis coli (APC) gene loss-driven ß-catenin activation in colorectal cancer, whereas TFRC-mediated intratumoral iron accumulation potentiates ß-catenin signaling by directly enhancing the activity of tankyrase. Disruption of TFRC leads to a reduction of colonic iron levels and iron-dependent tankyrase activity, which caused stabilization of axis inhibition protein 2 (AXIN2) and subsequent repression of the ß-catenin/c-Myc/E2F Transcription Factor 1/DNA polymerase delta1 (POLD1) axis. POLD1 knockdown, iron chelation, and TFRC disruption increase DNA replication stress, DNA damage response, apoptosis, and reduce colon tumor growth. Importantly, a combination of iron chelators and DNA damaging agents increases DNA damage response and reduces colon tumor cell growth. TFRC-mediated iron import is at the center of a novel feed-forward loop that facilitates colonic epithelial cell survival. This discovery may provide novel strategies for colorectal cancer therapy.