Claudin‐1, a Biomarker of Epithelial‐Mesenchymal Transformation, Enhances Lipid Metabolism in Colorectal Cancer Cells to Promote Tumor Metastasis

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Abstract
Claudin‐1 (CLDN1), a vital tight junction protein, is linked to epithelial‐mesenchymal transition (EMT) of tumor cells. In this study, multi‐omics including expression profiles of colorectal cancer (CRC) from The Cancer Genome Atlas (TCGA) dataset, colon expression profiles from the Genotype‐Tissue Expression (GTEx) database, and the expression profiles from the Gene Expression Omnibus (GEO) dataset GSE251845 were combined and analyzed. We screened for differentially expressed genes (DEGs) in CRC and identified 218 intersected genes related to EMT. Then, deep machine learning models, including least absolute shrinkage and selection operator (LASSO), random forest (RF), and support vector machine (SVM), were applied in depth screening, and 11 candidate genes were ultimately screened, including ADAM12, CD36, CLDN1, ETV4, FOXQ1, GLIPR2, MMP11, MMP7, NCL, SALL4, and SIM2. Functional annotation revealed that CLDN1 is closely associated with the AMP‐activated protein kinase (AMPK) and lipid metabolic pathways. Our validation experiments showed that CLDN1 was upregulated in human CRC tissues and cell lines compared with adjacent normal tissues and normal cell lines, and it promoted CRC cell proliferation, EMT, and lipid metabolism in vitro. Furthermore, administration of Compound C, an AMPK inhibitor, reversed the suppressive effects of CLDN1 knockdown on cell proliferation, EMT, and lipid metabolism, indicating the AMPK signaling pathway is involved in CLDN1‐mediated EMT and lipid metabolism in CRC cells. These findings suggest that CLDN1 plays a significant role in EMT and lipid metabolism of CRC cells and can be utilized as a therapeutic target for CRC.

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