PDF(Pubmed)
Abstract：
Sulfation is a crucial and prevalent conjugation reaction involved in cellular processes and mammalian physiology. 3\'-Phosphoadenosine 5\'-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the primary enzyme to generate the universal sulfonate donor PAPS. The involvement of PAPSS2-mediated sulfation in adenomatous polyposis coli (APC) mutation-promoted colonic carcinogenesis has not been reported. Here, we showed that the expression of PAPSS2 was decreased in human colon tumors along with cancer stages, and the lower expression of PAPSS2 was correlated with poor prognosis in advanced colon cancer. Gut epithelial-specific heterozygous Apc deficient and Papss2-knockout (ApcΔgut-HetPapss2Δgut) mice were created, and the phenotypes were compared to the spontaneous intestinal tumorigenesis of ApcΔgut-Het mice. ApcΔgut-HetPapss2Δgut mice were more sensitive to gut tumorigenesis, which was mechanistically accounted for by the activation of Wnt/β-catenin signaling pathway due to the suppression of chondroitin sulfation and inhibition of the farnesoid X receptor (FXR)-transducin-like enhancer of split 3 (TLE3) gene regulatory axis. Chondroitin sulfate supplementation in ApcΔgut-HetPapss2Δgut mice alleviated intestinal tumorigenesis. In summary, we have uncovered the protective role of PAPSS2-mediated chondroitin sulfation and bile acids-FXR-TLE3 activation in the prevention of gut carcinogenesis via the antagonization of Wnt/β-catenin signaling. Chondroitin sulfate may be explored as a therapeutic agent for Papss2 deficiency-associated colonic carcinogenesis.
摘要：
硫酸化是涉及细胞过程和哺乳动物生理学的关键和普遍的缀合反应。3'-磷酸腺苷5'-磷酸硫酸盐（PAPS）合酶2（PAPSS2）是产生通用磺酸盐供体PAPS的主要酶。尚未报道PAPSS2介导的硫酸化参与腺瘤性结肠息肉病（APC）突变促进的结肠癌发生。这里,我们发现PAPSS2的表达在人类结肠肿瘤中随着癌症分期而降低，PAPSS2的低表达与晚期结肠癌的不良预后有关。创建了肠上皮特异性杂合Apc缺陷和Papss2敲除（ApcΔgut-HetPapss2Δgut）小鼠，并将表型与ApcΔgut-Het小鼠的自发性肠道肿瘤发生进行了比较。ApcΔgut-HetPapss2Δgut小鼠对肠道肿瘤发生更敏感，这是由于抑制软骨素硫酸化和抑制法尼醇X受体（FXR）-转导素样分裂3（TLE3）基因调节轴而导致的Wnt/β-catenin信号通路的激活。在ApcΔgut-HetPapss2Δgut小鼠中补充硫酸软骨素可减轻肠道肿瘤发生。总之,我们发现了PAPSS2介导的软骨素硫酸化和胆汁酸-FXR-TLE3激活通过拮抗Wnt/β-catenin信号通路预防肠道癌变的保护作用.硫酸软骨素可作为Papss2缺乏相关结肠癌发生的治疗剂。
