Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Electrical and Computer Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania.
Cancer Immunol Res. 2020 Feb;8(2):167-178. doi: 10.1158/2326-6066.CIR-19-0514. Epub 2019 Dec 12.
Patients with ulcerative colitis have an increased risk of developing colitis-associated colon cancer (CACC). Changes in glycosylation of the oncoprotein MUC1 commonly occur in chronic inflammation, including ulcerative colitis, and this abnormally glycosylated MUC1 promotes cancer development and progression. It is not known what causes changes in glycosylation of MUC1. Gene expression profiling of myeloid cells in inflamed and malignant colon tissues showed increased expression levels of inflammatory macrophage-associated cytokines compared with normal tissues. We analyzed the involvement of macrophage-associated cytokines in the induction of aberrant MUC1 glycoforms. A coculture system was used to examine the effects of M1 and M2 macrophages on glycosylation-related enzymes in colon cancer cells. M2-like macrophages induced the expression of the glycosyltransferase ST6GALNAC1, an enzyme that adds sialic acid to O-linked GalNAc residues, promoting the formation of tumor-associated sialyl-Tn (sTn) O-glycans. Immunostaining of ulcerative colitis and CACC tissue samples confirmed the elevated number of M2-like macrophages as well as high expression of ST6GALNAC1 and the altered MUC1-sTn glycoform on colon cells. Cytokine arrays and blocking antibody experiments indicated that the macrophage-dependent ST6GALNAC1 activation was mediated by IL13 and CCL17. We demonstrated that IL13 promoted phosphorylation of STAT6 to activate transcription of ST6GALNAC1. A computational model of signaling pathways was assembled and used to test IL13 inhibition as a possible therapy. Our findings revealed a novel cellular cross-talk between colon cells and macrophages within the inflamed and malignant colon that contributes to the pathogenesis of ulcerative colitis and CACC..
溃疡性结肠炎患者发生结肠炎相关性结肠癌（CACC）的风险增加。oncoprotein MUC1 的糖基化在慢性炎症中经常发生改变，包括溃疡性结肠炎，这种异常糖基化的 MUC1 促进癌症的发展和进展。目前尚不清楚导致 MUC1 糖基化改变的原因。对炎症和恶性结肠组织中的髓样细胞进行基因表达谱分析显示，与正常组织相比，炎症巨噬细胞相关细胞因子的表达水平增加。我们分析了巨噬细胞相关细胞因子在诱导异常 MUC1 糖型中的作用。共培养系统用于研究 M1 和 M2 巨噬细胞对结肠癌细胞中糖基化相关酶的影响。M2 样巨噬细胞诱导糖基转移酶 ST6GALNAC1 的表达，该酶在 O-连接的 GalNAc 残基上添加唾液酸，促进肿瘤相关唾液酸化-Tn（sTn）O-聚糖的形成。溃疡性结肠炎和 CACC 组织样本的免疫染色证实了 M2 样巨噬细胞数量增加以及 ST6GALNAC1 和改变的 MUC1-sTn 糖型在结肠细胞上的高表达。细胞因子阵列和阻断抗体实验表明，IL13 和 CCL17 介导了巨噬细胞依赖性 ST6GALNAC1 激活。我们证明了 IL13 通过促进 STAT6 的磷酸化来激活 ST6GALNAC1 的转录。组装了信号通路的计算模型，并将其用于测试 IL13 抑制作为一种可能的治疗方法。我们的研究结果揭示了炎症和恶性结肠中结肠细胞和巨噬细胞之间的一种新的细胞串扰，这有助于溃疡性结肠炎和 CACC 的发病机制。
