Targeting IL-23 for the interception of obesity-associated colorectal cancer.
Targeting IL-23 for the interception of obesity-associated colorectal cancer.
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DOI：
10.1016/j.neo.2023.100939
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发表时间：
2023-11
期刊：
影响因子：
4.8
通讯作者：
Rao, Chinthalapally V.
中科院分区：
文献类型：
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作者：
Madka, Venkateshwar;Chiliveru, Srikanth;Panneerselvam, Janani;Pathuri, Gopal;Zhang, Yuting;Stratton, Nicole;Kumar, Nandini;Sanghera, Dharambir K.;Rao, Chinthalapally V.
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，IL-23在结直肠癌中显著升高，并与患者肥胖、肿瘤分级和生存期相关。因此，我们假设肥胖和结直肠癌可能通过炎症联系在一起，而IL-23可能是高危患者干预的潜在靶点。对TCGA数据集和患者血清进行IL-23A水平评估。将IL-23A[IL-23 p19−/−]基因敲除(KO)小鼠与Apcmin/+小鼠杂交，子代饲喂低脂或高脂饲料。在终止时，评估肠道的肿瘤形成情况。分别对肿瘤、血清和粪便内容物进行蛋白质生物标志物、细胞因子和微生物组图谱分析。肥胖和结肠肿瘤患者血清中IL-23A水平升高。IL-23A的基因消融显著抑制了雄性和雌性小鼠结肠肿瘤的多样性(76-96%)和发病率(72-95%)。同样，IL-23A KO小鼠的小肠肿瘤多样性和大小也显著降低。在喂饲高脂饲料的Apcmin/+小鼠中，IL-23A基因敲除也显著抑制了结肠(50-58%)和SI(41-48%)肿瘤的多样性。细胞因子分析显示，几种循环中的促炎细胞因子减少，包括丢失IL-23A。生物标记物分析显示，与对照组相比，IL-23A KO小鼠的肿瘤细胞增殖和免疫调节减少，肿瘤浸润性CD4+和CD8+T淋巴细胞增加。粪便微生物组分析显示，细菌种群结构发生了潜在的有益变化。综上所述，我们的数据表明IL-23在包括饮食诱导的肥胖在内的结直肠癌中具有促进肿瘤的作用。随着几种IL-23靶向治疗的临床试验，靶向这种细胞因子用于预防和治疗结直肠癌的潜力很大。
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.
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