TLR4 signaling promotes a COX-2/PGE₂/STAT3 positive feedback loop in hepatocellular carcinoma (HCC) cells

Abstract

Toll-like receptors (TLRs) can be expressed by tumor cells, and each TLR exhibits different biological functions. Evidences showed the activation of some certain TLRs could promote tumor progression. One of which TLR4 has been found to promote hepatocellular carcinoma (HCC) cells proliferation, but the detailed mechanism is still unknown. In the present study, we verified that TLR4 was functionally expressed on HCC cells, and TLR4 agonist lipopolysaccharide (LPS) could stimulate the proliferation and clone formation of HCC cells. Most importantly, we found a COX-2/PGE2/STAT3 positive feedback loop exists in HCC cells, which could be provoked by TLR4 activation. Consistently, the expression of TLR4, COX-2 and p-STAT3Y705 was positively correlated with each other in liver tumor tissues from patients with primary HCC. Further investigation demonstrated this loop played a dominant role in TLR4-induced HCC cell proliferation and multidrug resistance (MDR) to chemotherapy. Inhibition of TLR4 or COX-2/PGE2/STAT3 loop would attenuate LPS-induced inflammation and proliferation of HCC cells, and enhance the sensitivity of HCC cells to chemotherapeutics in vitro. By using a primary HCC model, we observed COX-2/PGE2/STAT3 loop was significantly blocked in TLR4−/− mice compared to wild type mice, and there was no obvious tumorgenesis sign in TLR4−/− mice. Therefore, these findings provided the precise molecular mechanism of TLR4 signaling pathway involved in HCC progress, and suggested that TLR4 may be a promising target for HCC treatment.

Hypoxia‐induced tRNA‐derived fragments, novel regulatory factor for doxorubicin resistance in triple‐negative breast cancer

“…STAT3 is known to be part of the HIF‐1α–DNA complex, which mediates the gene transcription functions of HIF‐1α, and its activation may confer hypoxia‐induced chemoresistance by upregulating ABC transporters, particularly ABCC2 and ABCC6 (Soleymani Abvaneh et al, ). As the target gene, KITLG promotes activation of STAT3, FGFR1OP leads to phosphorylation of STAT3, and TLR4 signaling promotes a COX‐2/PGE2/STAT3 positive feedback loop (Bossi et al, ; Cokic et al, ; Lin et al, ). Taken together, we hypothesized that tDR‐0009 (tDR‐7336) might be involved in the chemoresistance of TNBC via regulation of the activation of phosphorylation of STAT3.…”

Fungal pattern receptors down‐regulate the inflammatory response by a cross‐inhibitory mechanism independent of interleukin‐10 production

“…a). Given the prominent role of COX‐2 in the autocrine production of PGE 2 and in STAT3 activation, its expression was addressed. Zymosan and mannan were robust inducers, whereas mannose‐depleted zymosan was inactive (Fig.…”

IFN‐γ protects from apoptotic neutrophil‐mediated tissue injury during acute Listeria monocytogenes infection

“…The primers used were as follows: β ‐actin forward primer (5′‐ AGA GGG AAA TCG TGC GTG AC) and reverse primer (5′‐ CAA TAG TGA TGA CCT GGC CGT); Cxcl1 forward primer (5′‐ GCT TGA AGG TGT TGC CCT CAG) and reverse primer (5′‐ AGA AGC CAG CGT TCA CCA GAC); Il‐17a forward primer (5′‐ CAG CAG CGA TCA TCC CTC AAA G) and reverse primer (5′‐ CAG GAC CAG GAT CTC TTG CTG); iNos forward primer (5′‐ GGC AAA CCC AAG GTC TAC GTT) and reverse primer (5′‐ TCG CTC AAG TTC AGC TTG GT). The PCR conditions have been described previously .…”