TLR4 signaling promotes a COX-2/PGE(2)/STAT3 positive feedback loop in hepatocellular carcinoma (HCC) cells.
TLR4 signaling promotes a COX-2/PGE(2)/STAT3 positive feedback loop in hepatocellular carcinoma (HCC) cells.
复制标题
TLR4 信号传导促进肝细胞癌细胞 (HCC) 中的 COX-2/PGE(2)/STAT3 正反馈环
DOI：
10.1080/2162402x.2015.1074376
复制
发表时间：
2016-02
期刊：
影响因子：
7.2
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Lin A;Wang G;Zhao H;Zhang Y;Han Q;Zhang C;Tian Z;Zhang J
肿瘤细胞可表达Toll样受体(Toll-like Receptor，TLR)，每种TLR具有不同的生物学功能。有证据表明，某些TLRs的激活可以促进肿瘤的进展。其中之一的TLR4已被发现具有促进肝细胞癌(HCC)细胞增殖的作用，但具体机制尚不清楚。在本研究中，我们证实了TLR4在肝癌细胞上的功能性表达，并且TLR4激动剂脂多糖(LPS)可以刺激肝癌细胞的增殖和克隆形成。最重要的是，我们发现肝癌细胞中存在COX-2/PGE2/STAT3正反馈环，该环可能由TLR4激活引起。TLR4、COX-2和p-STAT3Y705在原发性肝癌患者肝肿瘤组织中的表达呈正相关。进一步研究表明，该环在TLR4诱导的肝癌细胞增殖和化疗多药耐药(MDR)中起主导作用。抑制TLR4或COX-2/PGE2/STAT3环可减轻脂多糖诱导的肝癌细胞的炎症和增殖，增强肝癌细胞对化疗药物的敏感性。在原代肝癌模型中，与野生型小鼠相比，TLR4−/−小鼠的COX-2/PGE_2/STAT3环被显著阻断，而TLR_4−/−小鼠没有明显的肿瘤形成迹象。因此，这些发现提供了TLR4信号通路参与肝癌进展的确切分子机制，并提示TLR4可能是肝癌治疗的一个有前途的靶点。
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.