Alcohol promotes epithelial mesenchymal transformation-mediated premetastatic niche formation of colorectal cancer by activating interaction between laminin-γ2 and integrin-β1.

Abstract

BACKGROUNDColorectal cancer (CRC) is a common malignant tumor. Alcohol consumption is positively correlated with CRC malignant metastasis; however, the mechanism is unclear. The interaction between laminin-γ2 (LAMC2) and integrin-β1 (ITGB1) plays a role in premetastatic niche signaling, which may induce epithelial mesenchymal transformation (EMT) and lead to metastasis.AIMTo investigate the effects of alcohol on CRC metastasis from the molecular mechanism of the premetastatic niche.METHODSThe interaction between LAMC2 and ITGB1 was measured by Duolink assay, and the expression levels of LAMC2, ITGB1 and focal adhesion kinase (FAK), snail, fibronectin, N-cadherin and special AT-rich sequence binding protein 1 (SATB1) were measured by quantitative real-time polymerase chain reaction, immunohistochemistry and western blotting. Interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and IL-6 levels were measured via enzyme-linked immunosorbent assay, histopathological assessment via hematoxylin eosin staining, and determination of aberrant crypt foci via methylene blue.RESULTSThe lymph node metastasis rate was higher in the alcohol group than non-alcohol group. There was a significant increase in interaction signals between LAMC2 and ITGB1, and an increase in phosphorylate-FAK/FAK, snail, fibronectin, N-cadherin and SATB1, whereas E-cadherin was reduced in the alcohol group compared to the non-alcohol group in both animal and clinical samples. Serum IL-1β, TNF-α and IL-6 were higher in alcohol group than in non-alcohol group. Alcohol may promote CRC metastasis by influencing the molecular mechanism of the premetastatic niche.CONCLUSIONOur study suggests that alcohol promotes EMT-mediated premetastatic niche formation of CRC by activating the early interaction between LAMC2 and ITGB1 and lead to CRC metastasis.