Colorectal Cancer Liver Metastasis-Associated Ferroptosis-Related Genes Modulate Lipid Peroxidation in Colorectal...

Area of Science:

• Oncology
• Cell Death Research
• Biomarker Discovery

Background:

• Distant metastasis, particularly to the liver, is the primary cause of death in colorectal cancer (CRC).
• Biomarkers for metastatic competence in CRC are limited.
• Ferroptosis, a regulated cell death form, can inhibit tumor growth, but its role in CRC liver metastasis resistance is unclear.

Purpose of the Study:

• Investigate ferroptosis resistance features in primary CRC tumors associated with liver metastasis.
• Identify novel biomarkers for colorectal cancer liver metastasis (CRC-LM).
• Explore the functional role of identified candidates in CRC cell models.

Main Methods:

• Analysis of primary CRC tumors for redox and lipid peroxidation markers, and ferroptosis-related protein expression (SLC7A11, GPX4).
• Integration of transcriptomic data (GSE62321) with ferroptosis gene sets (FerrDb) and TCGA-COAD/READ survival analysis.
• In vitro studies using CRC cell models involving genetic knockdown, lipid ROS staining, and migration/invasion assays.

Main Results:

• Primary CRC tumors with liver metastasis exhibited a more reduced redox profile and higher expression of ferroptosis suppressors.
• FABP4, SNCA, and DDR2 were identified as CRC-LM-associated ferroptosis-related candidates, with high expression linked to poor survival.
• Silencing FABP4, SNCA, or DDR2 in CRC cells increased lipid ROS, altered ferroptosis susceptibility, and reduced migration/invasion.

Conclusions:

• FABP4, SNCA, and DDR2 are potential biomarkers for colorectal cancer liver metastasis.
• These genes modulate lipid peroxidation and ferroptosis, influencing CRC cell migratory and invasive phenotypes.
• Further validation in controlled models is warranted to explore therapeutic potential.