TLR4 increases the stemness and is highly expressed in relapsed human hepatocellular carcinoma

Toll-like receptor 4 (TLR4) plays an essential role in cancer progress. Here, we find that the expression of TLR4 in relapsed human hepatocellular carcinoma (HCC) clinical samples is higher than that in the non-relapsed ones, which leads us to explore the role of TLR4 in cancer stemness. We reported that TLR4-AKT signaling pathway was activated by lipopolysaccharides (LPS) in HCC cell lines to enhance the cancer stemness capacity, which was reflected by the increased percentage of CD133⁺ CD49f⁺ population and side population, enhanced sphere formation, and the upregulation of stemness marker gene-SOX2. Downregulation of SOX2 attenuated the enhanced HCC stemness induced by LPS, indicating SOX2 as a downstream mediator of LPS-TLR4 signaling. The role of LPS-TLR4 signaling in inducing HCC stemness was further confirmed by tumor xenograft experiment in vivo. Taken together, our findings provide a novel therapeutic target to prevent the recurrence of HCC.