Toll-like receptor 4 signaling promotes epithelial-mesenchymal transition in human hepatocellular carcinoma induced by lipopolysaccharide

Abstract

BackgroundThe endotoxin level in the portal and peripheral veins of hepatocellular carcinoma (HCC) patients is higher and lipopolysaccharide (LPS), a cell wall constituent of gram-negative bacteria, has been reported to inhibit tumor growth. However, in this study, we found that LPS-induced toll-like receptor 4 (TLR4) signaling was involved in tumor invasion and survival, and the molecular mechanism was investigated,MethodsFour HCC cell lines and a splenic vein metastasis of the nude mouse model were used to study the invasion ability of LPS-induced HCC cells and the epithelia-mesenchymal transition (EMT) in vitro and in vivo. A total of 106 clinical samples from HCC patients were used to evaluate TLR4 expression and analyze its association with clinicopathological characteristicsResultsThe in vitro and in vivo experiments demonstrated that LPS could significantly enhance the invasive potential and induce EMT in HCC cells with TLR4 dependent. Further studies showed that LPS could directly activate nuclear factor kappa B (NF-κB) signaling through TLR4 in HCC cells. Interestingly, blocking NF-κB signaling significantly inhibited transcription factor Snail expression and thereby inhibited EMT occurrence. High expression of TLR4 in HCC tissues was strongly associated with both poor cancer-free survival and overall survival in patients.ConclusionsOur results indicate that TLR4 signaling is required for LPS-induced EMT, tumor cell invasion and metastasis, which provide molecular insights for LPS-related pathogenesis and a basis for developing new strategies against metastasis in HCC.

Platelets promote tumour metastasis via interaction between TLR4 and tumour cell-released high-mobility group box1 protein

“…Most studies linking TLR4 and its ligand LPS with metastasis 16,17 were focused on tumour cell TLR4. In the present study, we demonstrate that host TLR4 also plays a key role in supporting metastasis.…”

“…TLR4 activation on tumour cells facilitates escape from immune surveillance 26 and promotes EMT 17 . In accordance, LPS treatment in TLR4-null mice led to increased metastasis, although the amplitude was smaller than in WT mice.…”

“…Depending on the composition of the cells in the microenvironment and stage of disease, activation of TLR4 signalling can either stimulate 14 or inhibit 15 tumour development. Studies focusing on the endotoxin and tumour cell TLR4 have already shown that endotoxin is a potent promoter of tumour metastasis when infused systemically 16 , and that tumour cell TLR4 activation by endotoxin resulted in EMT of tumour cells and augmented metastasis 17 . Importantly, TLR4 can detect endogenous damage-associated molecular patterns including the widely expressed alarmin protein HMGB1 (ref.…”

LPS-induced CXCR4-dependent migratory properties and a mesenchymal-like phenotype of colorectal cancer cells

“…37 And, there have been studies which indicate that LPS can activate NF-kB pathway. 36,38 In order to verify whether LPS affect the occurrence of EMT and CXCR4 expression via NF-kB in C26 cells, we used western blot to detect NF-kB activity. The results showed that LPS activated p-IkB.…”

“…36 The NF-kB signaling pathway has been shown to be involved in tumor cells migration and invasion. 37 And, there have been studies which indicate that LPS can activate NF-kB pathway.…”