Intestinal Sulfation Is Essential to Protect Against Colitis and Colonic Carcinogenesis.
Intestinal Sulfation Is Essential to Protect Against Colitis and Colonic Carcinogenesis.
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DOI：
10.1053/j.gastro.2021.03.048
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发表时间：
2021-07
期刊：
影响因子：
29.4
通讯作者：
Xie W
中科院分区：
文献类型：
--
作者：
Xu P;Xi Y;Zhu J;Zhang M;Luka Z;Stolz DB;Cai X;Xie Y;Xu M;Ren S;Huang Z;Yang D;York JD;Ma X;Xie W
硫酸化是哺乳动物中许多生化和细胞功能所必需的缀合反应。3'-磷酸腺苷5'-磷酸硫酸酯（PAPS）合酶2（PAPSS 2）是产生PAPS的关键酶，PAPS是所有硫酸化反应的通用磺酸盐供体。本研究的目的是确定PAPSS2是否以及如何在结肠炎和结肠癌发生中发挥作用。分析了人类结肠癌标本的组织阵列、基因表达数据和癌症患者的临床特征。建立肠特异性Papss2基因敲除小鼠（Papss2 Δ IE），并使其经受葡聚糖硫酸钠（DSS）诱导的结肠炎，以及由氧化偶氮甲烷（AOM）和DSS联合治疗或单独AOM诱导的结肠癌发生。PAPSS2的表达在小鼠和人的结肠癌中降低。PAPSS 2在结肠癌患者中的低表达与较差的生存相关。Papss2 Δ IE小鼠表现出对结肠炎和结肠癌的高度敏感性，其通过破坏肠粘膜屏障、增加肠通透性和细菌浸润以及恶化肠肿瘤微环境来实现。从机制上讲，Papss2 Δ IE小鼠表现出肠道磺粘蛋白含量降低。代谢组学分析显示，Papss 2 Δ IE小鼠结肠中胆汁酸（包括法尼醇X受体（FXR）拮抗剂胆汁酸牛磺-β-鼠胆酸（T-β-MCA））蓄积，以及胆汁酸硫酸盐形成不足。我们已经发现了PAPSS2介导的硫酸化在结肠炎和结肠癌发生中的重要作用。肠硫酸化可能是一个潜在的诊断标志物，PAPSS2可能作为炎症性肠病和结肠癌的潜在治疗靶点。
Sulfation is a conjugation reaction essential for numerous biochemical and cellular functions in mammals. The 3’-phosphoadenosine 5’-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the key enzyme to generate PAPS, which is the universal sulfonate donor for all sulfation reactions. The goal of this study is to determine whether and how PAPSS2 plays a role in colitis and colonic carcinogenesis. Tissue arrays of human colon cancer specimens, gene expression data, and clinical features of cancer patients were analyzed. Intestinal-specific Papss2 knockout mice (Papss2ΔIE) were created and subjected to dextran sodium sulfate (DSS)-induced colitis, and colonic carcinogenesis induced by combined treatment of azoxymethane (AOM) and DSS, or AOM alone. The expression of PAPSS2 is decreased in the colon cancers of mice and humans. The lower expression of PAPSS2 in colon cancer patients is correlated with worse survival. Papss2ΔIE mice showed heightened sensitivity to colitis and colon cancer by damaging the intestinal mucosal barrier, increasing intestinal permeability and bacteria infiltration, and worsening the intestinal tumor microenvironment. Mechanistically, the Papss2ΔIE mice exhibited reduced intestinal sulfomucin content. Metabolomic analyses revealed the accumulation of bile acids including the farnesoid X receptor (FXR) antagonist bile acid tauro-β-muricholic acid (T-β-MCA), and deficiency in the formation of bile acid-sulfates in the colon of Papss2ΔIE mice. We have uncovered an important role of PAPSS2-mediated sulfation in colitis and colonic carcinogenesis. Intestinal sulfation may represent a potential diagnostic marker, and PAPSS2 may serve as a potential therapeutic target for inflammatory bowel disease and colon cancer.
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影响因子：
29.4
作者：
Li G;Liu D;Kimchi ET;Kaifi JT;Qi X;Manjunath Y;Liu X;Deering T;Avella DM;Fox T;Rockey DC;Schell TD;Kester M;Staveley-O'Carroll KF
通讯作者：
Staveley-O'Carroll KF
影响因子：
4.4
作者：
Lee, A;Beck, L;Markovich, D
通讯作者：
Markovich, D
影响因子：
11.5
作者：
Hong, Yi;Ho, Kok Sun;Cheah, Peh Yean
通讯作者：
Cheah, Peh Yean
影响因子：
--
作者：
Leung AW;Backstrom I;Bally MB
通讯作者：
Bally MB
影响因子：
64.8
作者：
Godinho-Silva, Cristina;Domingues, Rita G.;Veiga-Fernandes, Henrique
通讯作者：
Veiga-Fernandes, Henrique