TLR4 signaling promotes a COX-2/PGE2/STAT3 positive feedback loop in hepatocellular carcinoma(HCC) cells
作者单位：Institute of Immunopharmaceutical Sciences School of Pharmaceutical Sciences Shandong University
会议名称：《第十届全国免疫学学术大会》
会议日期：2015年
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
关 键 词：TLR4 HCC Proliferation Multidrug Resistance STAT3
摘 要：Background Hepatocellular carcinoma(HCC) is the fifth most common cancer worldwide and ranks second among all the primary cancer-related mortalities. The high recurrence and poor prognosis of HCC accentuate the need to clarify the pathogenesis and develop new therapeutic approaches. Toll-like receptors(TLRs), expressed by a great variety of immune cells, have also been found in many tumor tissues and cell lines. Evidences showed that intestinal microecological disorder would affect HCC progression, during which TLR4 signaling pathway might play an important role. AIM To investigate the underlying mechanism of TLR4 signaling pathway in HCC development. Methods Human hepatoma cell lines Hep G2 and H7402 as well as TLR4-/- mice were used in this study. Cell prolifera-tion was analyzed by WST-1 assay. Real-time quantitative PCR, Western blot, Immunohistochemistry and ELISA methods were used to analyze the expression levels of molecules associated with TLR4 signaling. Results In this study, we found a COX-2/PGE2/STAT3 positive feedback loop exists in HCC cells, which could be provoked by TLR4 activation. Consistently, TLR4, COX-2 and p-STAT3 were highly expressed in primary HCC tumor tissues compared to adjacent non-tumor sites, and positively correlated with each other. Further investigation demonstrated this loop played a dominant role in TLR4-induced HCC cell proliferation and multidrug resistance(MDR) of HCC to chemotherapeutics in vitro. Importantly, 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. Moreover, specific silence or inhibition of TLR4 could increase the sensitivity of HCC to chemotherapeutics in vitro. Conclusion These findings clarified one critical mechanism of TLR4 signaling pathway involved in HCC progress, which may provide new sights for HCC clinical treatment and development of novel liver-targeted anti-t