Department of Gastroenterology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, 110004, Shenyang, China.
Department of Gastroenterology, The Second Affiliated Hospital of Shenyang Medical College, Shenyang, China.
Cell Mol Biol Lett. 2022 Sep 5;27(1):75. doi: 10.1186/s11658-022-00374-0.
Ulcerative colitis-associated colorectal cancer (UC-CRC) is an important complication of ulcerative colitis. Pou3f1 (POU class 3 homeobox 1) is a critical regulator for developmental events and cellular biological processes. However, the role of Pou3f1 in the development of UC-CRC is unclear.
In vivo, a UC-CRC mouse model was induced by azoxymethane (AOM) and dextran sulfate sodium (DSS). Body weight, colon length, mucosal damage, tumor formation, and survival rate were assessed to determine the progression of UC-CRC. Western blot, quantitative real-time PCR, ELISA, immunohistochemistry, immunofluorescence and TUNEL were performed to examine the severity of inflammation and tumorigenesis. In vitro, LPS-treated mouse bone marrow-derived macrophages (BMDMs) and RAW264.7 cells were used to study the role of Pou3f1 in inflammation. ChIP and luciferase reporter assays were used to confirm the interaction between Nfatc3 and Pou3f1.
Pou3f1 expression was increased in the colons of UC-CRC mice, and its inhibition attenuated mucosal injury, reduced colon tumorigenesis and increased survival ratio. Knockdown of Pou3f1 suppressed cell proliferation and increased cell death in colon tumors. Both the in vivo and in vitro results showed that Pou3f1 depletion reduced the production of proinflammation mediators. In addition, ChIP and luciferase reporter assays demonstrated that Nfatc3 directly bound with the Pou3f1 promoter to induce its expression. The effect of Nfatc3 on the inflammatory response in macrophages was suppressed by Pou3f1 knockdown.
Overall, it outlines that Pou3f1 mediates the role of Nfatc3 in regulating macrophage inflammation and carcinogenesis in UC-CRC development.
溃疡性结肠炎相关结直肠癌（UC-CRC）是溃疡性结肠炎的重要并发症。Pou3f1（POU 类 3 同源框 1）是发育事件和细胞生物学过程的关键调节因子。然而，Pou3f1 在 UC-CRC 发展中的作用尚不清楚。
在体内，通过使用偶氮甲烷（AOM）和葡聚糖硫酸钠（DSS）诱导 UC-CRC 小鼠模型。通过评估体重、结肠长度、黏膜损伤、肿瘤形成和存活率来确定 UC-CRC 的进展情况。通过 Western blot、定量实时 PCR、ELISA、免疫组织化学、免疫荧光和 TUNEL 来检测炎症和肿瘤发生的严重程度。在体外，使用 LPS 处理的小鼠骨髓来源的巨噬细胞（BMDMs）和 RAW264.7 细胞来研究 Pou3f1 在炎症中的作用。使用 ChIP 和荧光素酶报告基因检测来确认 Nfatc3 与 Pou3f1 之间的相互作用。
Pou3f1 在 UC-CRC 小鼠的结肠中表达增加，其抑制作用可减轻黏膜损伤、减少结肠肿瘤发生并提高存活率。Pou3f1 敲低可抑制结肠肿瘤中的细胞增殖并增加细胞死亡。体内和体外结果均表明，Pou3f1 耗竭可减少促炎介质的产生。此外，ChIP 和荧光素酶报告基因检测表明，Nfatc3 直接与 Pou3f1 启动子结合以诱导其表达。巨噬细胞中 Nfatc3 对炎症反应的作用被 Pou3f1 敲低所抑制。
总之，该研究概述了 Pou3f1 介导了 Nfatc3 在调节 UC-CRC 发展中巨噬细胞炎症和癌变中的作用。
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