7097

TLR2

toll-like receptor 2;TLR2;toll-like receptor 2

toll/interleukin 1 receptor-like 4|toll/interleukin-1 receptor-like protein 4

4q32

protein-coding

Chronic bacterial infection increased the risk of many solid malignancies and the underlying mechanism is usually ascribed to bacterial-caused inflammation. However, the direct interaction of infectious bacteria with cancer cells has been largely overlooked. We identified that highly metastatic breast cancer MDA-MB-231 cells expressed high level of Toll-like receptor 2 (TLR2) in contrast to poorly metastatic breast cancer cells and homogenous untransformed breast cells. TLR2 in MDA-MB-231 cells were actively triggered by peptidoglycan (PGN) from infectious bacterium Staphylococcus aureus (PGN-SA), resulting in the promoted invasiveness and adhesiveness of the cancer cells in vitro. PGN-SA induced phosphorylation of TAK1 and IkappaB in the TLR2-NF-kappaB pathway of the cancer cells and stimulated IL-6 and TGF-beta secretion in MDA-MB-231 cells. All these effects were abrogated by TLR2 blockade. Further investigation showed that the NF-kappaB, STAT3 and Smad3 activities were augmented sequentially in MDA-MB-231 cells after PGN-SA stimulation. Phosphorylation of NF-kappaBp65 was initially increased and then followed by phosphorylation of STAT3 and Smad3 in the delayed 4 or 6 hours. NF-kappaB inhibition attenuated STAT3 and Smad3 activities whereas PGN-SA-stimulated cell culture supernatants reversed these inhibitory effects. Our study indicated that TLR2 activation by infectious bacterial PGN played an important role in breast cancer cell invasiveness and illustrated a new link between infectious bacteria and the cancer cells, suggesting the importance of antibiotic therapy to treat cancer with bacterial infection.

Toll-like receptors (TLRs) play a key role in cancer metastasis. The biological role of TLR2 in invasion and metastasis in gastric carcinoma cells and gastric carcinoma is not clear; therefore, we aimed to investigate the biological role of TLR2 in invasion by SGC-7901 human gastric carcinoma cells and to determine whether TLR2 is associated with gastric carcinoma metastasis. RT-PCR, real-time PCR, flow cytometry, and western blotting showed that TLR2 activation significantly increased TLR2 expression at the mRNA and protein levels and notably promoted the transcription of genes related to angiogenesis and invasion, such as VEGF-C and MMP-9. The invasive capacity of SGC-7901 cells was strikingly advanced by TLR2 stimulation on Transwell invasion assay. IL-6 in the supernatants of cultured SGC-7901 cells was increased under the condition of TLR2 stimulation and reduced after TLR2 blockade by ELISA. Combined with clinicopathological parameters, the expression of TLR2 protein examined by immunohistochemical analysis was higher in gastric carcinoma tissues than in adjacent non-cancerous tissues (p<0.001). There was a significant relationship between TLR2 expression and lymph node metastasis (p<0.01), distant metastasis (p<0.01). There was no significant correlation between gastric carcinoma and age (p>0.05), sex (p>0.05), or degree of differentiation (p>0.05). These findings indicate that TLR2 may participate in the progression and metastasis of human gastric carcinoma and provide a new therapeutic target against metastasis of gastric carcinoma.

Inflammation is a part of the host defense system, which provides protection against invading pathogens. However, it has become increasingly clear that inflammation can be evoked by endogenous mediators through Toll-like receptors (TLRs) to enhance tumor progression and metastasis. Here, we discuss the roles of TLR-mediated inflammation in tumor progression and the mechanisms through which it accomplishes this pathogenic function.