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Abstract：
Inflammation and obesity are two major factors that promote Colorectal cancer (CRC). Our recent data suggests that interleukin (IL)-23, is significantly elevated in CRC tumors and correlates with patient obesity, tumor grade and survival. Thus, we hypothesize that obesity and CRC may be linked via inflammation and IL-23 may be a potential target for intervention in high-risk patients. TCGA dataset and patient sera were evaluated for IL-23A levels. IL-23A [IL-23 p19-/-] knockout (KO) mice were crossed to Apcmin/+ mice and progeny were fed low-fat or high-fat diets. At termination intestines were evaluated for tumorigenesis. Tumors, serum, and fecal contents were analyzed for protein biomarkers, cytokines, and microbiome profile respectively. IL-23A levels are elevated in the sera of patients with obesity and colon tumors. Genetic ablation of IL-23A significantly suppressed colonic tumor multiplicity (76-96 %) and incidence (72-95 %) in male and female mice. Similarly, small-intestinal tumor multiplicity and size were also significantly reduced in IL-23A KO mice. IL-23A knockdown in Apcmin/+ mice fed high-fat diet, also resulted in significant suppression of colonic (50-58 %) and SI (41-48 %) tumor multiplicity. Cytokine profiling showed reduction in several circulating pro-inflammatory cytokines including loss of IL-23A. Biomarker analysis suggested reduced tumor cell proliferation and immune modulation with an increase in tumor-infiltrating CD4+ and CD8+ T-lymphocytes in the IL-23A KO mice compared to controls. Fecal microbiome analysis revealed potentially beneficial changes in the bacterial population profile. In summary, our data indicates a tumor promoting role for IL-23 in CRC including diet-induced obesity. With several IL-23 targeted therapies in clinical trials, there is a great potential for targeting this cytokine for CRC prevention and therapy.
摘要：
炎症和肥胖是促进结直肠癌（CRC）的两个主要因素。我们最近的数据表明，白细胞介素（IL）-23在CRC肿瘤中显著升高，并与患者肥胖相关。肿瘤分级和生存率。因此，我们假设肥胖和CRC可能通过炎症相关,IL-23可能是高危患者干预的潜在靶点.评估TCGA数据集和患者血清的IL-23A水平。将IL-23A[IL-23p19-/-]敲除(KO)小鼠与Apcmin/+小鼠杂交,并给后代喂食低脂肪或高脂肪饮食。在终止时,评价肠的肿瘤发生。肿瘤,血清,和粪便内容物分析蛋白质生物标志物，细胞因子,和微生物组概况。肥胖和结肠肿瘤患者血清中IL-23A水平升高。IL-23A的遗传消融显着抑制雄性和雌性小鼠的结肠肿瘤多重性（76-96％）和发生率（72-95％）。同样，在IL-23AKO小鼠中，小肠肿瘤的多样性和大小也显着降低。高脂饮食喂养的Apcmin/+小鼠的IL-23A敲低，还导致结肠（50-58％）和SI（41-48％）肿瘤多重性的显着抑制。细胞因子谱分析显示几种循环促炎细胞因子的减少,包括IL-23A的损失。生物标志物分析表明，与对照组相比，IL-23AKO小鼠的肿瘤细胞增殖和免疫调节降低，肿瘤浸润性CD4和CD8T淋巴细胞增加。粪便微生物组分析揭示了细菌种群谱的潜在有益变化。总之,我们的数据表明IL-23在包括饮食诱导的肥胖在内的CRC中具有肿瘤促进作用.随着几种IL-23靶向疗法的临床试验，靶向该细胞因子用于CRC预防和治疗的潜力巨大.
