肠道免疫失调与肿瘤的发生和形成密切相关。环指蛋白 128 (RNF128) 已被鉴定在先天和适应性系统中发挥独特的免疫调节功能。然而，RNF128在结肠炎和结直肠癌（CRC）等肠道炎症性疾病中的生理作用仍存在争议。阐明RNF128在结肠炎和CRC中的功能和机制。右旋糖酐硫酸钠（DSS）诱导的结肠炎和氧化偶氮甲烷的动物模型(AOM)/DSS 诱导的 CRC 在 WT 和 Rnf128 缺陷小鼠中建立，并通过组织病理学进行评估。采用免疫共沉淀和泛素化分析来研究 RNF128 在 IL-6-STAT3 信号传导中的作用。与配对的瘤周组织相比，RNF128 在临床 CRC 组织中显着下调。 Rnf128缺陷小鼠对DSS诱导的结肠炎和AOM/DSS或APC突变诱导的CRC高度敏感。在 IL-6 刺激下，RNF128 的缺失促进了体内和体外癌发生早期转化阶段的 CRC 细胞增殖和 STAT3 激活。从机制上讲，RNF128与IL-6受体α亚基（IL-6Rα）和膜糖蛋白gp130相互作用，并以连接酶活性依赖性方式介导它们的溶酶体降解。通过IL-6受体的一系列点突变，我们发现RNF128促进IL-6Rα的K398/K401处和gp130的K718/K816/K866处的K48连接的多泛素化。此外，阻断 STAT3 激活可有效消除 Rnf128 缺陷小鼠在癌变转化阶段的炎症损伤。RNF128 通过抑制 IL-6-STAT3 信号传导来减轻结肠炎和结直肠肿瘤发生，这为 IL-6 受体和结直肠癌的调节提供了新的见解。炎症到癌症的转变。版权所有 © 2024。由 Elsevier B.V. 制作和托管

Intestinal immune dysregulation is strongly linked to the occurrence and formation of tumors. RING finger protein 128 (RNF128) has been identified to play distinct immunoregulatory functions in innate and adaptive systems. However, the physiological roles of RNF128 in intestinal inflammatory conditions such as colitis and colorectal cancer (CRC) remain controversial.To elucidate the function and mechanism of RNF128 in colitis and CRC.Animal models of dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced CRC were established in WT and Rnf128-deficient mice and evaluated by histopathology. Co-immunoprecipitation and ubiquitination analyses were employed to investigate the role of RNF128 in IL-6-STAT3 signaling.RNF128 was significantly downregulated in clinical CRC tissues compared with paired peritumoral tissues. Rnf128-deficient mice were hypersusceptible to both colitis induced by DSS and CRC induced by AOM/DSS or APC mutation. Loss of RNF128 promoted the proliferation of CRC cells and STAT3 activation during the early transformative stage of carcinogenesis in vivo and in vitro when stimulated by IL-6. Mechanistically, RNF128 interacted with the IL-6 receptor α subunit (IL-6Rα) and membrane glycoprotein gp130 and mediated their lysosomal degradation in ligase activity-dependent manner. Through a series of point mutations in the IL-6 receptor, we identified that RNF128 promoted K48-linked polyubiquitination of IL-6Rα at K398/K401 and gp130 at K718/K816/K866. Additionally, blocking STAT3 activation effectively eradicated the inflammatory damage of Rnf128-deficient mice during the transformative stage of carcinogenesis.RNF128 attenuates colitis and colorectal tumorigenesis by inhibiting IL-6-STAT3 signaling, which sheds novel insights into the modulation of IL-6 receptors and the inflammation-to-cancer transition.Copyright © 2024. Production and hosting by Elsevier B.V.