Biology Research Institute of the United Laboratories International Holdings Limited, Zhuhai, China.
PLoS One. 2010 May 26;5(5):e10850. doi: 10.1371/journal.pone.0010850.
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.
慢性细菌感染增加了许多实体恶性肿瘤的风险，其潜在机制通常归因于细菌引起的炎症。然而，传染性细菌与癌细胞的直接相互作用在很大程度上被忽视了。我们发现，高度转移性乳腺癌 MDA-MB-231 细胞表达高水平的 Toll 样受体 2（TLR2），与低转移性乳腺癌细胞和同质未转化的乳腺细胞形成对比。TLR2 在 MDA-MB-231 细胞中被感染细菌金黄色葡萄球菌（PGN-SA）的肽聚糖（PGN）主动激活，导致癌细胞在体外的侵袭性和黏附性增强。PGN-SA 在 TLR2-NF-κB 通路中诱导 TAK1 和 IkappaB 的磷酸化，并刺激 MDA-MB-231 细胞中 IL-6 和 TGF-β的分泌。TLR2 阻断可消除所有这些效应。进一步的研究表明，在 PGN-SA 刺激后，NF-κB、STAT3 和 Smad3 活性在 MDA-MB-231 细胞中依次增强。NF-κBp65 的磷酸化最初增加，然后在延迟 4 或 6 小时后 STAT3 和 Smad3 的磷酸化增加。NF-κB 抑制减弱了 STAT3 和 Smad3 的活性，而 PGN-SA 刺激的细胞培养上清液则逆转了这些抑制作用。我们的研究表明，传染性细菌 PGN 对 TLR2 的激活在乳腺癌细胞侵袭性中起重要作用，并说明了感染性细菌与癌细胞之间的新联系，这表明抗生素治疗在治疗细菌感染相关癌症方面的重要性。
