Proteomics-driven discovery of LCAT as a novel biomarker for liver metastasis in colorectal cancer.

Background: This study aimed to identify molecular markers that influence liver metastasis in colorectal cancer (CRC) and assess their clinical relevance.

Methods: Proteomic analysis compared differential protein expression between CRC patients with liver metastasis (CRLM) and those without (CRNLM). Bioinformatics and survival analyses identified key proteins and validated them using the TCGA database for expression and clinical significance. Clinical and pathological data, along with tissue samples from our center, were used to create tissue microarrays for immunohistochemistry. Logistic regression assessed odds ratios (OR) for molecular markers linked to liver metastasis post-CRC surgery. Stable LCAT knockdown and overexpression CRC cell lines were constructed, and Transwell assays assessed the impact LCAT on cell migration. Nile red staining of these cells validated the effect LCAT on lipid metabolism in CRC cells.

Results: Proteomic analysis identified 383 differentially expressed proteins between the CRLM and CRNLM groups (212 upregulated, 171 downregulated). Enrichment analysis linked these proteins to steroid and alcohol metabolism, inflammation, lipoproteins, and HDL particles, with key pathways in cholesterol and retinol metabolism. Lecithin cholesterol acyltransferase (LCAT), an important enzyme in this process, showed higher expression in CRC tissues, with increased LCAT linked to poorer 5-year OS, DSS, and PFI. LCAT expression also increased with tumor stage. Among 119 patients with CRC, preoperative complications, tumor staging, and LCAT scores differed significantly between patients with and without liver metastasis within 3 years post-surgery. LCAT and postoperative CEA levels were independent risk factors for liver metastasis (LCAT OR, 10.221; P = 0.002; CEA OR, 1.296; P = 0.014). Western blotting confirmed significantly higher LCAT expression in CRC tissues with liver metastasis. Transwell assays showed that LCAT overexpression enhanced migratory ability, while knockdown inhibited it. Nile red staining revealed increased lipid droplet accumulation in LCAT-overexpressing CRC cells, which was reduced by LCAT knockdown.

Conclusion: LCAT, which is involved in lipid metabolism, is an independent risk factor for liver metastasis following CRC surgery, suggesting its potential as a therapeutic target.