Department of Pharmacy - Division of Biomedicine "Arturo Leone", University of Salerno, Fisciano (SA), Italy.
PLoS One. 2013 Nov 13;8(11):e79455. doi: 10.1371/journal.pone.0079455. eCollection 2013.
The trefoil peptides (TFF1, TFF2 and TFF3) are a family of small highly conserved proteins that play an essential role in epithelial regeneration within the gastrointestinal tract, where they are mainly expressed. TFF1 expression is strongly induced after mucosal injury and it has been proposed that tff1 functions as a gastric tumor suppressor gene. Several studies confirm that tff1 expression is frequently lost in gastric cancer because of deletions, mutations or methylation of the tff1 promoter. Infection by Helicobacter pylori (H. pylori) results in chronic gastritis and it can lead to the development of gastric or duodenal ulcers. Moreover, it is known that there is a strong link to the development of gastric cancer. It has been shown that H. pylori interacts with the dimeric form of TFF1 and that the rough form of lipopolysaccharide mediates this interaction. We have previously reported that the carboxy-terminus of TFF1 is able to specifically bind copper ions (Cu) and that Cu binding favours the homodimerization of the peptide, thus enhancing its motogenic activity. Here, we report that the Cu-TFF1 cuprocomplex promotes adherence of H. pylori to epithelial cells. Adherence of H. pylori to gastric adenocarcinoma cells, AGS AC1 cells, induced to hyper-express TFF1 was enhanced compared to noninduced cells. Copper further promoted this interaction. A H. pylori mutant unable to bind TFF1 did not show enhanced infection of induced cells. Cu treatment induced a thickening of the mucus layer produced by the colorectal adenocarcinoma mucus secreting, goblet cells, HT29-E12 and promoted H. pylori colonisation. Finally, SPR analysis shows that the C-terminus of TFF1, involved in the binding of copper, is also able to selectively bind H. pylori RF-LPS.
三叶肽（TFF1、TFF2 和 TFF3）是一小族高度保守的蛋白质，在胃肠道的上皮再生中发挥着重要作用，主要在胃肠道中表达。TFF1 的表达在黏膜损伤后强烈诱导，并且已经提出 tff1 作为胃肿瘤抑制基因发挥作用。几项研究证实，由于 tff1 启动子的缺失、突变或甲基化，tff1 在胃癌中经常丢失。幽门螺杆菌（H. pylori）的感染会导致慢性胃炎，并可能导致胃或十二指肠溃疡的发展。此外，已知与胃癌的发展有很强的联系。已经表明 H. pylori 与 TFF1 的二聚体形式相互作用，并且粗糙形式的脂多糖介导这种相互作用。我们之前报道过 TFF1 的羧基末端能够特异性结合铜离子（Cu），并且 Cu 结合有利于肽的同源二聚化，从而增强其运动活性。在这里，我们报告 TFF1 的 Cu-TFF1 铜复合物促进 H. pylori 对上皮细胞的粘附。与非诱导细胞相比，诱导高表达 TFF1 的胃腺癌细胞 AGS AC1 细胞中 H. pylori 的粘附增强。铜进一步促进了这种相互作用。不能结合 TFF1 的 H. pylori 突变体显示出对诱导细胞的感染增强。Cu 处理诱导结直肠腺癌黏液分泌、杯状细胞 HT29-E12 产生的黏液层变厚，并促进 H. pylori 定植。最后，SPR 分析表明，TFF1 的 C 末端参与铜结合，也能够选择性地结合 H. pylori RF-LPS。
