A20 Restricts NOS2 Expression and Intestinal Tumorigenesis in a Mouse Model of Colitis-Associated Cancer.
A20 Restricts NOS2 Expression and Intestinal Tumorigenesis in a Mouse Model of Colitis-Associated Cancer.
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DOI：
10.1016/j.gastha.2022.09.004
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Shao, Ling
中科院分区：
文献类型：
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作者：
Basta, David W;Vong, Mandy;Beshimova, Adolat;Nakamura, Brooke N;Rusu, Iulia;Kattah, Michael G;Shao, Ling
结肠癌可以零星发生，也可以在慢性炎症的情况下发生，例如在患有炎症性肠病的患者中。我们以前的研究表明，A20是肿瘤坏死因子信号转导的关键负调节因子，可以调节散发性结肠癌的发展。在这份报告中，我们调查是否A20也作为结肠炎相关癌症模型中的肿瘤抑制因子。使用葡聚糖硫酸钠和氧化偶氮甲烷在野生型和A20肠上皮细胞特异性敲除（A20dIEC）小鼠中诱导结肠炎和结肠炎相关肿瘤。炎症的临床病理学标志物与结肠肿瘤负荷一起评估。对结肠组织和肠上皮进行基因表达分析和免疫组化。在全结肠裂解物和小鼠胚胎成纤维细胞中评估一氧化氮（NO）的产生和活性。用葡聚糖硫酸钠和氧化偶氮甲烷治疗后，A20dIEC小鼠比野生型小鼠产生更大的肿瘤。除了升高的炎症标志物外，A20dIEC小鼠还显著增强了诱导型一氧化氮合酶（iNOS）的表达，这是一种众所周知的肿瘤形成驱动因素。诱导型一氧化氮合酶表达增强与活性氮的形成和DNA损伤有关。A20的缺失也直接增强NO依赖性细胞死亡。从机制上讲，我们认为A20通常限制肠上皮细胞中肿瘤坏死因子诱导的核因子κ B依赖性iNOS的产生，从而防止结肠炎相关的肿瘤发生。我们还提出，A20在调节NO依赖性细胞死亡中起直接作用。
Colon cancer can occur sporadically or in the setting of chronic inflammation, such as in patients with inflammatory bowel disease. We previously showed that A20, a critical negative regulator of tumor necrosis factor signal transduction, could regulate sporadic colon cancer development. In this report, we investigate whether A20 also acts as a tumor suppressor in a model of colitis-associated cancer. Colitis and colitis-associated tumors were induced in wild-type and A20 intestinal epithelial cell-specific knockout (A20dIEC) mice using dextran sodium sulfate and azoxymethane. Clinicopathologic markers of inflammation were assessed in conjunction with colonic tumor burden. Gene expression analyses and immunohistochemistry were performed on colonic tissue and intestinal enteroids. Nitric oxide (NO) production and activity were assessed in whole colonic lysates and mouse embryonic fibroblasts. A20dIEC mice develop larger tumors after treatment with dextran sodium sulfate and azoxymethane than wild-type mice. In addition to elevated markers of inflammation, A20dIEC mice have significantly enhanced expression of inducible nitric oxide synthase (iNOS), a well-known driver of neoplasia. Enhanced iNOS expression is associated with the formation of reactive nitrogen species and DNA damage. Loss of A20 also enhances NO-dependent cell death directly. Mechanistically, we propose that A20 normally restricts tumor necrosis factor–induced nuclear factor kappa B–dependent production of iNOS in intestinal epithelial cells, thereby protecting against colitis-associated tumorigenesis. We also propose that A20 plays a direct role in regulating NO-dependent cell death.