Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Jiefang Road, Wuhan, Hubei 430022, China.
Pancreatology. 2012 Mar-Apr;12(2):170-8. doi: 10.1016/j.pan.2012.02.015. Epub 2012 Mar 2.
BACKGROUND & AIMS: Hypoxia is a common characteristic of solid tumors. Recent studies confirmed that Toll-like receptor 4 (TLR4) plays a significant role in cancer invasion and progression. In this study, the correlation between the expression of TLR4 and the change of the protein level of Hypoxia-inducible factor-1 alpha (HIF-1α) was studied.
We examined 84 human pancreatic cancer tissues for expression of HIF-1α and TLR4 proteins. Panc-1 cells were exposed to normoxia (20% O(2)) or hypoxia (<1% O(2)) or treated with CoCl(2). TLR4 protein was analyzed by flow cytometry and immunostaining. Growth studies were conducted on cells with the HIF-1α inhibition isolated from stable transfected cell lines. Finally, TLR4 protein was detected by immunohistochemistry in vivo tumors.
There was a positive correlation between TLR4 and HIF-1α protein in pancreatic cancer tissues. Hypoxic stress induced TLR4 mRNA and protein expression in Panc-1 cells. Cells transfected with HIF-1α siRNA showed attenuation of hypoxia stress-induced TLR4 expression. In vivo growth decreased in response to TLR4 and HIF-1α inhibiton. Transient HIF-1α siRNA treatment could effectively curb tumor growth in vivo.
These results suggest that TLR4 expression in pancreatic cancer cells is up-regulated via HIF-1α in response to hypoxic stress and underscore the crucial role of HIF-1α-induced TLR4 in tumor growth.
缺氧是实体肿瘤的一个共同特征。最近的研究证实 Toll 样受体 4（TLR4）在癌症侵袭和进展中起重要作用。在本研究中，研究了 TLR4 的表达与缺氧诱导因子-1α（HIF-1α）蛋白水平变化之间的相关性。
我们检测了 84 个人胰腺癌细胞组织中 HIF-1α 和 TLR4 蛋白的表达。将 Panc-1 细胞暴露于常氧（20% O2）或缺氧（<1% O2）或用 CoCl2 处理。通过流式细胞术和免疫染色分析 TLR4 蛋白。从稳定转染细胞系中分离出具有 HIF-1α 抑制作用的细胞进行生长研究。最后，通过免疫组织化学法检测体内肿瘤中的 TLR4 蛋白。
在胰腺癌组织中 TLR4 和 HIF-1α 蛋白之间存在正相关。缺氧应激诱导 Panc-1 细胞 TLR4 mRNA 和蛋白表达。转染 HIF-1α siRNA 的细胞显示缺氧应激诱导的 TLR4 表达减弱。对 TLR4 和 HIF-1α 的抑制作用导致体内生长减少。短暂的 HIF-1α siRNA 处理可有效抑制体内肿瘤生长。
这些结果表明，胰腺癌细胞中 TLR4 的表达通过 HIF-1α 对缺氧应激的反应而上调，并强调了 HIF-1α 诱导的 TLR4 在肿瘤生长中的关键作用。
