Increased Expression of Toll-Like Receptor 4 in Hepatocellular Carcinoma ─ Its Clinicopathological Significance ─

Lipopolysaccharide (LPS), known as endotoxin, is produced by Gram-negative bacteria and transported from the intestine to the liver via the portal vein. While LPS is cytotoxic and gives damages to hepatocytes, it also functions as an exogenous ligand for toll-like receptor 4 (TLR4) expressed in the plasma membrane. Stimulated by LPS, TLR4 activates MyD88-NF-κB signaling pathway in hepatocytes, leading to tissue repair and cell proliferation. It has thus been postulated that a combination of LPS-induced hepatic injury and TLR4-mediated tissue repair may lead to development of hepatocellular carcinoma (HCC). As recently reported, the increased expression of TLR4 in HCC is related to poor prognosis, suggesting involvement of TLR4 in HCC progression after its development. To explore correlation of clinicopathological characteristics of HCC with TLR4 expression, we immunostained TLR4 protein in both HCC and its neighboring non-cancerous area by using 99 resected livers bearing HCC. In general, TLR4 expression was significantly higher in HCC areas than in non-cancerous areas. When correlation of the increased expression of TLR4 with different clinicopathological factors was assessed, tumor size and expanding growth pattern were significantly correlated with the TLR4 expression level, suggesting that TLR4 is closely related to cell proliferation but not invasive phenotype.