Thanki Ketan K, Johnson Paul, Higgins Edward J, Maskey Manjit, Phillips Ches'Nique, Dash Swetaleena, Almenas Francisco Arroyo, Govar Armita Abdollahi, Tian Bing, Villéger Romain, Beswick Ellen, Wang Rui, Szabo Csaba, Chao Celia, Pinchuk Irina V, Hellmich Mark R, Módis Katalin
Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
Department of Internal Medicine, University of Texas Medical, Galveston, TX, USA.
Redox Biol. 2022 Sep;55:102417. doi: 10.1016/j.redox.2022.102417. Epub 2022 Jul 21.
Ulcerative colitis (UC) is characterized by widespread relapsing inflammation of the colonic mucosa. Colitis-associated cancer (CAC) is one of the most serious complications of a prolonged history of UC. Hydrogen sulfide (HS) has emerged as an important physiological mediator of gastrointestinal homeostasis, limiting mucosal inflammation and promoting tissue healing in response to injury. Inhibition of cystathionine-γ-lyase (CSE)-dependent HS production in animal models of UC has been shown to exacerbate colitis and delay tissue repair. It is unknown whether CSE plays a role in CAC, or the downregulation of CSE expression and/or activity promotes CAC development. In humans, we observed a significant decrease in CSE expression in colonic biopsies from patients with UC. Using the dextran sodium sulfate (DSS) model of epithelium injury-induced colitis and global CSE KO mouse strain, we demonstrated that CSE is critical in limiting mucosal inflammation and stimulating epithelial cell proliferation in response to injury. In vitro studies showed that CSE activity stimulates epithelial cell proliferation, basal and cytokine-stimulated cell migration, as well as cytokine regulation of transepithelial permeability. In the azoxymethane (AOM)/DSS model of CAC, the loss of CSE expression accelerated both the development and progression of CAC. The increased tumor multiplicity and severity of CAC observed in CSE-KO mice were associated with reduced levels of mucosal IL-10 expression and increased levels of IL-6. Restoring CSE expression in bone marrow (BM) cells of CSE-KO mice through reciprocal BM transplantation raised mucosal IL-10 expression, decreased IL-6 level, and reduced the number of aberrant crypt foci and tumors in AOM/DSS-treated mice. These studies demonstrate that CSE expression in BM cells plays a critical role in suppressing CAC in mice. Furthermore, the data suggest that the inhibitory effects of CSE on the development of CAC are due, in part, to the modulation of mucosal pro-and anti-inflammatory cytokine expression.
溃疡性结肠炎（UC）的特征是结肠黏膜广泛复发炎症。结肠炎相关癌（CAC）是UC病程延长最严重的并发症之一。硫化氢（HS）已成为胃肠道稳态的重要生理介质，可限制黏膜炎症并促进损伤后的组织愈合。在UC动物模型中，抑制胱硫醚-γ-裂解酶（CSE）依赖性HS生成已被证明会加重结肠炎并延迟组织修复。目前尚不清楚CSE在CAC中是否起作用，或者CSE表达和/或活性的下调是否会促进CAC的发展。在人类中，我们观察到UC患者结肠活检中CSE表达显著降低。使用上皮损伤诱导的结肠炎右旋糖酐硫酸钠（DSS）模型和全球CSE基因敲除小鼠品系，我们证明CSE在限制黏膜炎症和刺激损伤后的上皮细胞增殖中起关键作用。体外研究表明，CSE活性可刺激上皮细胞增殖、基础和细胞因子刺激的细胞迁移，以及细胞因子对跨上皮通透性的调节。在CAC的氧化偶氮甲烷（AOM）/DSS模型中，CSE表达缺失加速了CAC的发生和发展。在CSE基因敲除小鼠中观察到的CAC肿瘤多重性增加和严重程度与黏膜IL-10表达水平降低和IL-6水平升高有关。通过相互骨髓移植恢复CSE基因敲除小鼠骨髓（BM）细胞中的CSE表达，可提高黏膜IL-10表达，降低IL-6水平，并减少AOM/DSS处理小鼠中异常隐窝灶和肿瘤的数量。这些研究表明，BM细胞中的CSE表达在抑制小鼠CAC中起关键作用。此外，数据表明CSE对CAC发展的抑制作用部分归因于对黏膜促炎和抗炎细胞因子表达的调节。
