TRAP1 controls the crosstalk between SDHA/HIF-1α, HIF/ERK1/2/Twist, and HIF/FoxC/Twist pathways via HIF-1α during EMT in colorectal cancer

Abstract

Abstract Background Tumor necrosis factor receptor-associated protein 1 (TRAP1) is highly-expressed during epithelial-mesenchymal transition (EMT) in colorectal cancer (CRC). Here, we investigated the mechanism underlying the high expression of TRAP1 during EMT and evaluated the potential of TRAP1 as a therapeutic target for metastatic CRC treatment. Moreover, we discussed ways to improve the clinical effectiveness of CRC treatments. Methods HCT116 colon cancer cell lines (either over-expressing or lacking TRAP1), nude mouse tumor experiments, and human CRC tissue were used. The effect of TRAP1 gene expression on the migration of CRC cells was studied using methods characterizing cellular function. The mechanism of the effect of TRAP1 expression on EMT in CRC was studied using immunohistochemistry, immunofluorescence, and western blotting methods. Results High TRAP1 expression was found to increase the migration of CRC cells, reduce apoptosis rates, regulate the E-cadherin and vimentin expression in opposite directions, as well as increase expression levels of hypoxia inducible factor 1α (HIF-1α), extracellular signal-regulated kinase 1/2 (ERK1/2), Twist, forkhead box protein C2 (FoxC2), and reduce the expression of succinate dehydrogenase complex flavoprotein subunit A (SDHA) proteins. These results indicate that TRAP1 regulates EMT in CRC by affecting the crosstalk between SDHA/HIF-1α, HIF/ERK1/2/Twist, and HIF/FOXC/Twist pathways. Conclusion High TRAP1 expression was found to promote EMT in CRC. TRAP1 activates expression of genes encoding proteins involved in SDHA/HIF-1α, HIF-1α/ERK1/2/Twist/Snail, and HIF-1α/FoxC/Twist/Snail pathways via HIF-1α. TRAP1 also regulates the expression of E-cadherin, the downstream protein of EMT.