Kruppel-like factor 9 (KLF9) prevents colorectal cancer through inhibition of interferon-related signaling
Kruppel-like factor 9 (KLF9) prevents colorectal cancer through inhibition of interferon-related signaling
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DOI：
10.1093/carcin/bgv104
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发表时间：
2015-09-01
期刊：
影响因子：
4.7
通讯作者：
Simmen, Frank A.
中科院分区：
文献类型：
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作者：
Brown, Adam R.;Simmen, Rosalia C. M.;Simmen, Frank A.
转录因子kruppel样因子9 （KLF9）的表达在结直肠癌中经常降低，尽管其抑瘤作用尚未确定。为了确定KLF9是否抑制肠腺瘤的形成，我们在Apc（Min/+）小鼠的背景下产生了不同KLF9基因型的小鼠，并比较了它们在16周龄时的腺瘤负荷。虽然在Klf9基因型中小肠腺瘤负荷保持不变，但雄性和雌性Apc(Min/+)/Klf9（-/-）和Apc(Min/+)/Klf9（+/-）小鼠比Apc(Min/+)/Klf9（+/+）小鼠表现出更多的结肠腺瘤。微阵列分析显示，在腺瘤发生前，雌性Apc(Min/+)/Klf9（+/-）和Apc(Min/+)/Klf9（-/-）小鼠结肠黏膜中干扰素诱导基因的表达显著高于Apc(Min/+)/Klf9（+/+）小鼠。在人HT29结直肠癌细胞中，结肠粘膜qPCR和KLF9 siRNA敲低证实了基因上调。这些基因的表达增加通过补充干扰素β 1进一步增强。相对于Apc(Min/+)/Klf9（+/+）和Apc(Min/+)/Klf9（-/-）小鼠，Apc(Min/+)/Klf9（+/+）的循环细胞因子干扰素刺激基因15 （ISG15）水平升高。此外，Apc(Min/+)/Klf9（+/-）小鼠结肠黏膜ISG15水平升高。染色质免疫沉淀显示KLF9募集到ISG15启动子。最后，在5-氟尿嘧啶（5FU）存在和不存在的情况下，ISG15治疗可抑制HT29细胞的凋亡。结果表明，KLF9是Apc（Min/+）小鼠结肠肿瘤发生的单倍不足抑制因子，部分原因是通过抑制ISG15和后者的抗凋亡功能。
Expression of the transcription factor Kruppel-like factor 9 (KLF9) is frequently reduced in colorectal cancers, although a tumor suppressive role has not been established. To determine if KLF9 suppresses intestinal adenoma formation, we generated mice of distinct Klf9 genotypes in the background of the Apc(Min/+) mouse and compared their adenoma burdens at 16 weeks of age. While small intestine adenoma burden remained unchanged among Klf9 genotypes, male and female Apc(Min/+)/Klf9(-/-) and Apc(Min/+)/Klf9(+/-) mice exhibited significantly more colon adenomas than their Apc(Min/+)/Klf9(+/+) counterparts. Microarray analysis showed significant increases in the expression of interferon-induced genes in the colon mucosa of female Apc(Min/+)/Klf9(+/-) and Apc(Min/+)/Klf9(-/-)compared to Apc(Min/+)/Klf9(+/+)mice, prior to overt adenoma occurrence. Gene upregulation was confirmed by qPCR of colon mucosa and by siRNA knockdown of KLF9 in human HT29 colorectal cancer cells. Increases in expression of these genes were further augmented by supplementation with Interferon beta 1. Circulating levels of the cytokine, interferon-stimulated gene 15 (ISG15) were increased in Apc(Min/+)/Klf9(+/-) and Apc(Min/+)/Klf9(-/-) mice relative to Apc(Min/+)/Klf9(+/+). Additionally, colon mucosal levels of ISG15 were increased in Apc(Min/+)/Klf9(+/-) mice. Chromatin immunoprecipitation demonstrated KLF9 recruitment to the ISG15 promoter. Lastly, treatment with ISG15 suppressed apoptosis in HT29 cells, in the presence and absence of 5-fluorouracil (5FU). Results show KLF9 to be a haploinsufficient suppressor of colon tumorigenesis in Apc(Min/+) mice in part, by repression of ISG15 and the latter's antiapoptotic function.