TLR4/NF-kB/β-Catenin/TGF-β pathways in Salmonella AvrA related-Colorectal Cancer Tumorigenesis

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer mortality due to cancer after lung cancer. Understanding detailed pathomechanisms concerned with chronic Salmonella infection, which is known to play a crucial role in CRC tumorigenesis related to AvrA protein, can contribute to the advanced management of CRC. This study aimed to find the effect of Salmonella AvrA protein on the occurrence of CRC through the TLR4/NF-кB/β-catenin/TGF-β pathway by analyzing whether it is empirically consistent with the theory through path analysis from the CRC mice model. The immunohistochemistry method was used for data collection for TLR4, β-catenin, NF-кB, TGF-β, Ki67, and apoptotic cells. Data were analyzed by creating a path analysis. A significant direct effect was shown by the expression of TLR4 to β-catenin (p=0.000), β-catenin to NF-кB (p=0.000), and TGF-β to Ki67 (p=0.000). In addition, this also occurred in the expression of NF-кB to Ki67 (p=0.000) and the apoptotic percentage (p=0.020). The indirect effect was shown by the expression of TLR4 to NF-кB through β-catenin (R=0.724; p=0.000). In addition, the expression of β-catenin on Ki67 through NF-кB (R=0.364; p=0.000) and β-catenin to the apoptotic percentage through NF-кB expression (R= –0.633; p=0.042). These studies explain the effect of giving Salmonella AvrA to CRC mice model through the crosstalk involvement of TLR4, β-catenin, NF-кB, TGF-β, and Ki67 pathway. The direct and indirect effects show consistent evidence between the Salmonella infection in the CRC mice model and the theory. Salmonella activates the TLR4 and β-catenin pathways, triggering NF-кB pathways crucial for immune regulation, inflammation, and cell differentiation. The increased TLR4, β-catenin, NF-кB, and TGF-β pathway also correlated with the tumor progressivity, indicated by increased Ki67 and decreased apoptotic percentage. In conclusion, the overexpression of all pathways above by Salmonella AvrA leads to uncontrolled cell proliferation and apoptosis inhibition, consequently promoting CRC tumorigenesis.