BGN/TLR4/NF-κB Mediates Epigenetic Silencing of Immunosuppressive Siglec Ligands in Colon Cancer Cells
BGN/TLR4/NF-κB Mediates Epigenetic Silencing of Immunosuppressive Siglec Ligands in Colon Cancer Cells
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DOI：
10.3390/cells9020397
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发表时间：
2020-02-01
期刊：
影响因子：
6
通讯作者：
Kannagi, Reiji
中科院分区：
文献类型：
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作者：
Huang, Hsiang-Chi;Cai, Bi-He;Kannagi, Reiji
人类toll样受体（TLR）信号通过激活nf - κ B通路在肠道炎症中起重要作用。通过查询GENT2数据集，我们发现TLR2和TLR4基因表达水平在结直肠癌中显著升高。引入TLR4而非TLR2的shrna可显著恢复双芳醛Lewis(a)和6-磺酰Lewis(x)聚糖，这两种聚糖在非恶性结肠上皮细胞中优先表达，可作为免疫抑制分子siglece -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，并参与了Siglec-7配体的表观遗传沉默。抑制BGN的表达可显著下调参与这些聚糖合成的SLC26A2和ST6GalNAc6基因启动子区域的NF-kappa B活性和标记物H3K27me3，恢复正常聚糖的表达和siglece -7的结合活性。我们发现，在TLR4存在的情况下，炎症刺激启动一个涉及NF-kappa B的正循环，激活BGN并进一步增强TLR4活性。目前的研究结果表明，通过BGN/TLR4/ NF-kappa B途径的免疫抑制配体丧失促进癌变的推测机制。
Human Toll-like receptor (TLR) signaling plays a vital role in intestinal inflammation by activating the NF-kappa 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 Lewis(a) and sialyl 6-sulfo Lewis(x) 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-kappa 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-kappa 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-kappa B pathway.