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Abstract：
Human Toll-like receptor (TLR) signaling plays a vital role in intestinal inflammation by activating the NF-B pathway. By querying GENT2 datasets, we identified the gene expression level of TLR2 and TLR4 as being substantially increased in colorectal cancer. Introduction of shRNAs for TLR4 but not TLR2 dramatically recovered disialyl Lewisa and sialyl 6-sulfo Lewisx glycans, which are preferentially expressed in non-malignant colonic epithelial cells and could serve as ligands for the immunosuppressive molecule Siglec-7. We screened several TLR4 ligands and found that among them BGN is highly expressed in cancers and is involved in the epigenetic silencing of Siglec-7 ligands. Suppression of BGN expression substantially downregulated NF-B activity and the marker H3K27me3 in the promoter regions of the SLC26A2 and ST6GalNAc6 genes, which are involved in the synthesis of those glycans, and restored expression of normal glycans as well as Siglec-7 binding activities. We show that in the presence of TLR4, inflammatory stimuli initiate a positive loop involving NF-B that activates BGN and further enhances TLR4 activity. Present findings indicate a putative mechanism for the promotion of carcinogenesis by loss of immunosuppressive ligands by the BGN/TLR4/ NF-B pathway.
摘要：
人Toll样受体（TLR）信号通过激活NF-B通路在肠道炎症中起着至关重要的作用。通过查询GENT2数据集，我们发现结直肠癌中TLR2和TLR4的基因表达水平显著升高.引入shRNA用于TLR4而不是TLR2，显着回收二唾液酸Lewisa和唾液酸6-磺基Lewisx聚糖，其优先在非恶性结肠上皮细胞中表达,并且可以作为免疫抑制分子Siglec-7的配体。我们筛选了几种TLR4配体，发现其中BGN在癌症中高表达，并参与Siglec-7配体的表观遗传沉默。抑制BGN表达显著下调SLC26A2和ST6GalNAc6基因启动子区的NF-B活性和标记H3K27me3，参与这些聚糖的合成，并恢复正常聚糖的表达以及Siglec-7结合活性。我们表明，在TLR4的存在下，炎症刺激会引发涉及NF-B的正环，从而激活BGN并进一步增强TLR4活性。目前的发现表明了通过BGN/TLR4/NF-B途径失去免疫抑制配体促进致癌作用的推定机制。
