Berberine inhibits colitis-associated tumorigenesis via suppressing inflammatory responses and the consequent EGFR signaling-involved tumor cell growth
Berberine inhibits colitis-associated tumorigenesis via suppressing inflammatory responses and the consequent EGFR signaling-involved tumor cell growth
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小檗碱通过抑制炎症反应和随后的 EGFR 信号传导相关的肿瘤细胞生长来抑制结肠炎相关的肿瘤发生
DOI：
10.1038/labinvest.2017.71
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发表时间：
2017-11-01
影响因子：
5
通讯作者：
Hu, Tianhui
中科院分区：
文献类型：
--
作者：
Li, Dandan;Zhang, Youyu;Hu, Tianhui
在病理性肠组织中分别发现了中药小檗碱的抗炎和抗肿瘤作用。然而，小檗碱的抗炎作用是否有助于其对结肠炎相关结直肠癌（CACRC）的抗肿瘤作用仍不清楚。在本研究中，我们发现小檗碱有效地抑制结肠炎相关的肿瘤发生和结肠上皮细胞过度增殖葡聚糖硫酸钠（DSS）治疗的Apc Min/+小鼠。一项机制研究发现，小檗碱的这些抑制作用是通过阻断结肠巨噬细胞中白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的表达而发生的。一项关于细胞系的体外研究发现，小檗碱处理Raw 264.7巨噬细胞导致条件培养基对具有杂合Apc突变的细胞系（Immorto-Min结肠上皮，IMCE）具有较少的增殖作用。EGFR-ERK信号传导途径作用于小檗碱/促炎细胞因子轴下游，调节CACRC细胞增殖。此外，在DSS治疗的Apc Min/+小鼠体内施用IL-6有效地削弱了小檗碱对结肠组织中肿瘤发生和EGFR-ERK信号传导的抑制作用。总之，我们的研究结果表明，小檗碱通过干扰肿瘤细胞生长中炎症反应驱动的EGFR信号传导来抑制CACRC的发展。这项研究的结果支持黄连素和其他抗炎药物可能有益于治疗CACRC的可能性。
The anti-inflammatory and anti-tumor effects of berberine, a traditional Chinese medicine, were separately discovered in pathological intestinal tissues. However, whether the anti-inflammatory effect of berberine contributes to its anti-tumor effect on colitis-associated colorectal cancer (CACRC) remains unknown. In the present study, we found that berberine effectively inhibited colitis-associated tumorigenesis and colonic epithelium hyperproliferation in dextran sulfate sodium (DSS)-treated Apc Min/+ mice. A mechanistic study identified that these inhibitory effects of berberine occurred through blocking interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in colonic macrophages. An in vitro study on cell lines identified that berberine treatment of Raw 264.7 macrophages resulted in conditioned media with fewer proliferative effects on a cell line with a heterozygous Apc mutation (Immorto-Min colonic epithelium, IMCE). EGFR-ERK signaling act downstream of berberine/pro-inflammatory cytokines axis to regulate CACRC cell proliferation. Furthermore, in vivo administration of IL-6 to DSS-treated Apc Min/+ mice effectively weakened the inhibitory effects of berberine on tumorigenesis and EGFR-ERK signaling in colon tissues. Altogether, the results of our studies have revealed that berberine inhibits the development of CACRC by interfering with inflammatory response-driven EGFR signaling in tumor cell growth. The findings of this study support the possibility that berberine and other anti-inflammatory drugs may be beneficial in the treatment of CACRC.