PDF(Pubmed)
Abstract：
Abnormalities in mucosal immunity are involved in the onset and progression of ulcerative colitis (UC), resulting in a high incidence of colorectal cancer (CRC). While high-mobility group box-1 (HMGB1) is overexpressed during colorectal carcinogenesis, its role in UC-related carcinogenesis remains unclear. In the present study, we investigated the role of HMGB1 in UC-related carcinogenesis and sporadic CRC. Both the azoxymethane colon carcinogenesis and dextran sulfate sodium colitis carcinogenesis models demonstrated temporal increases in mucosal HMGB1 levels. Activated CD8+ cells initially increased and then decreased, whereas exhausted CD8+ cells increased. Additionally, we observed increased regulatory CD8+ cells, decreased naïve CD8+ cells, and decreased mucosal epithelial differentiation. In the in vitro study, HMGB1 induced energy reprogramming from oxidative phosphorylation to glycolysis in CD8+ cells and intestinal epithelial cells. Furthermore, in UC dysplasia, UC-related CRC, and hyperplastic mucosa surrounding human sporadic CRC, we found increased mucosal HMGB1, decreased activated CD8+ cells, and suppressed mucosal epithelial differentiation. However, we observed increased activated CD8+ cells in active UC mucosa. These findings indicate that HMGB1 plays an important role in modulating mucosal immunity and epithelial dedifferentiation in both UC-related carcinogenesis and sporadic CRC.
摘要：
粘膜免疫异常与溃疡性结肠炎（UC）的发病和进展有关，导致结直肠癌（CRC）的高发病率。虽然高迁移率族蛋白B1（HMGB1）在大肠癌发生过程中过度表达，其在UC相关癌变中的作用尚不清楚.在本研究中,我们研究了HMGB1在UC相关癌变和散发性CRC中的作用。偶氮甲烷结肠癌和葡聚糖硫酸钠结肠炎癌变模型均显示粘膜HMGB1水平暂时增加。激活的CD8+细胞最初增加，然后减少，而耗尽的CD8+细胞增加。此外,我们观察到调节性CD8+细胞增加，减少幼稚CD8+细胞，粘膜上皮分化降低。在体外研究中，HMGB1诱导CD8+细胞和肠上皮细胞从氧化磷酸化到糖酵解的能量重编程。此外，在UC发育不良中，UC相关CRC，和人类散发性CRC周围的增生性粘膜，我们发现粘膜HMGB1增加，激活的CD8+细胞减少，并抑制粘膜上皮分化。然而,我们观察到活跃的UC粘膜中激活的CD8+细胞增加。这些发现表明HMGB1在调节UC相关癌变和散发性CRC的粘膜免疫和上皮去分化中起重要作用。
