Mao Fei, Xu Min, Zuo Xiangsheng, Yu Jiang, Xu Weiguo, Moussalli Micheline J, Elias Elias, Li Haiyan S, Watowich Stephanie S, Shureiqi Imad
Departments of *Gastrointestinal Medical Oncology, Pathology, and Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.
Departments of *Gastrointestinal Medical Oncology, Pathology, and Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
FASEB J. 2015 Jun;29(6):2359-70. doi: 10.1096/fj.14-264515. Epub 2015 Feb 24.
The IL-6/signal transducer and activator of transcription 3 (STAT3) pathway is a critical signaling pathway for colitis-associated colorectal cancer (CAC). Peroxisome proliferator-activated receptor (PPAR)-δ, a lipid nuclear receptor, up-regulates IL-6. 15-Lipoxygenase-1 (15-LOX-1), which is crucial to production of lipid signaling mediators to terminate inflammation, down-regulates PPAR-δ. 15-LOX-1 effects on IL-6/STAT3 signaling and CAC tumorigenesis have not been determined. We report that intestinally targeted transgenic 15-LOX-1 expression in mice inhibited azoxymethane- and dextran sodium sulfate-induced CAC, IL-6 expression, STAT3 phosphorylation, and IL-6/STAT3 downstream target (Notch3 and MUC1) expression. 15-LOX-1 down-regulation was associated with IL-6 up-regulation in human colon cancer mucosa. Reexpression of 15-LOX-1 in human colon cancer cells suppressed IL-6 mRNA expression, STAT3 phosphorylation, IL-6 promoter activity, and PPAR-δ mRNA and protein expression. PPAR-δ overexpression in colonic epithelial cells promoted CAC tumorigenesis in mice and increased IL-6 expression and STAT3 phosphorylation, whereas concomitant 15-LOX-1 expression in colonic epithelial cells (15-LOX-1-PPAR-δ-Gut mice) suppressed these effects: the number of tumors per mouse (mean ± sem) was 4.22 ± 0.68 in wild-type littermates, 6.67 ± 0.83 in PPAR-δ-Gut mice (P = 0.026), and 2.25 ± 0.25 in 15-LOX-1-PPAR-δ-Gut mice (P = 0.0006). Identification of 15-LOX-1 suppression of PPAR-δ to inhibit IL-6/STAT3 signaling-driven CAC tumorigenesis provides mechanistic insights that can be used to molecularly target CAC.
白细胞介素6/信号转导与转录激活因子3（STAT3）信号通路是结肠炎相关结直肠癌（CAC）的关键信号通路。过氧化物酶体增殖物激活受体（PPAR）-δ是一种脂质核受体，可上调白细胞介素6。15-脂氧合酶-1（15-LOX-1）对产生脂质信号介质以终止炎症至关重要，它可下调PPAR-δ。15-LOX-1对白细胞介素6/STAT3信号传导和CAC肿瘤发生的影响尚未确定。我们报告称，在小鼠中肠道靶向性转基因表达15-LOX-1可抑制由氧化偶氮甲烷和葡聚糖硫酸钠诱导的CAC、白细胞介素6表达、STAT3磷酸化以及白细胞介素6/STAT3下游靶点（Notch3和MUC1）的表达。在人类结肠癌黏膜中，15-LOX-1下调与白细胞介素6上调相关。在人类结肠癌细胞中重新表达15-LOX-1可抑制白细胞介素6 mRNA表达、STAT3磷酸化、白细胞介素6启动子活性以及PPAR-δ mRNA和蛋白表达。结肠上皮细胞中PPAR-δ过表达可促进小鼠CAC肿瘤发生，并增加白细胞介素6表达和STAT磷酸化，而在结肠上皮细胞中同时表达15-LOX-1（15-LOX-1-PPAR-δ-Gut小鼠）可抑制这些作用：野生型同窝小鼠每只小鼠的肿瘤数量（平均值±标准误）为4.22±0.68，PPAR-δ-Gut小鼠为6.67±0.83（P = 0.026），15-LOX-1-PPAR-δ-Gut小鼠为2.25±0.25（P = 0.0006）。确定15-LOX-1通过抑制PPAR-δ来抑制白细胞介素6/STAT3信号驱动的CAC肿瘤发生，为可用于对CAC进行分子靶向治疗提供了机制性见解。
