Therapeutic potential and deleterious effect of glucocorticoids on azoxymethane/dextran sulfate sodium-induced colorectal cancer in mice.
Therapeutic potential and deleterious effect of glucocorticoids on azoxymethane/dextran sulfate sodium-induced colorectal cancer in mice.
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发表时间：
2021
影响因子：
5.3
通讯作者：
Jun Pu;Xin-Ke Zhou;Jiaxin Liu;P. Hou;Meiju Ji
中科院分区：
文献类型：
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作者：
Jun Pu;Xin-Ke Zhou;Jiaxin Liu;P. Hou;Meiju Ji
糖皮质激素（GCs）广泛用于治疗各种自身免疫性疾病和炎症性疾病，包括炎症性肠病（IBD）。然而，GCs对结肠炎相关结直肠癌（CAC）进展的影响尚未得到很好的探讨。在本研究中，我们首先建立了偶氮甲烷和葡聚糖硫酸钠（AOM/DSS）诱导的小鼠结肠直肠癌模型和DSS诱导的小鼠结肠炎模型。然后在不同时期给予地塞米松（DEX）以确定其对肿瘤发生和肿瘤进展的影响。同时记录小鼠的体重、粪便特性和粪血。在本研究结束时，评估肿瘤的数量和负荷，并分析与细胞增殖相关的蛋白的表达。通过检测促炎细胞因子TNFα水平和炎性细胞的粘膜浸润来评价结肠炎症的发生。我们的研究结果显示，AOM注射后3次饮用含1.5% DSS的水成功诱导小鼠结肠和直肠多发肿瘤的形成。DEX早期和晚期干预均抑制小鼠结直肠肿瘤生长，下调PCNA和cyclin D1的表达。此外，DEX治疗显著抑制tnf - α的产生、炎症细胞的粘膜浸润和MAPK/JNK通路的活性，尤其是早期DEX干预。然而，我们也发现DEX治疗恶化了小鼠的一般状态，表现为更大的体重减轻和直肠出血。综上所述，早期和晚期DEX干预都能显著改善结肠炎症，抑制AOM/ dss诱导的结直肠癌的进展，至少部分原因是抑制了MAPK/JNK通路。值得注意的是，对小鼠一般状况的有害影响可能会限制GCs治疗的持续时间。
Glucocorticoids (GCs) are widely used in the treatment of various autoimmune and inflammatory diseases, including inflammatory bowel disease (IBD). However, the effect of GCs on the progression of colitis-associated colorectal cancer (CAC) has not been well explored. In this study, we first established a colorectal cancer model induced by azoxymethane and dextran sulfate sodium (AOM/DSS) and a colitis model induced by DSS in mice. Dexamethasone (DEX) was then administered at different periods of time to determine its effect on tumorigenesis and tumor progression. Meanwhile, body weight, stool property and fecal blood of mice were recorded. At the end of this study, the number and load of tumors were evaluated, and the expression of proteins associated with cell proliferation was analyzed. To evaluate the inflammation in colon, we detected the level of pro-inflammatory cytokine TNFα, and the mucosal infiltration of inflammatory cells. Our results revealed that AOM injection followed by three cycles of drinking water containing 1.5% DSS successfully induced multiple tumor formation in mouse colon and rectum. Both early and late DEX intervention suppressed tumor growth in mouse colorectum, and downregulated the expression of PCNA and cyclin D1. Moreover, DEX treatment significantly inhibited TNFα production, mucosal infiltration of inflammatory cells, and the activity of MAPK/JNK pathway, particularly early DEX intervention. However, we also found that DEX treatment deteriorated the general state of mouse manifested by greater loss of body weight and rectal bleeding. In summary, both early and late DEX interventions significantly ameliorate colonic inflammation and inhibit the progression of AOM/DSS-induced colorectal cancer, at least partly due to the inhibition of MAPK/JNK pathway. It is noteworthy that the deleterious effect on the general condition of mouse may limit the duration of GCs treatment.