Inhibition of nuclear factor-κB signaling suppresses Spint1-deletion-induced tumor susceptibility in the ApcMin/+ model.
Inhibition of nuclear factor-κB signaling suppresses Spint1-deletion-induced tumor susceptibility in the ApcMin/+ model.
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DOI：
10.18632/oncotarget.11863
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发表时间：
2016-10-18
期刊：
影响因子：
--
通讯作者：
Kataoka H
中科院分区：
文献类型：
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作者：
Kawaguchi M;Yamamoto K;Kanemaru A;Tanaka H;Umezawa K;Fukushima T;Kataoka H
肝细胞生长因子激活因子抑制剂1型（HAI-1）是一种表达于上皮细胞表面的膜结合丝氨酸蛋白酶抑制剂，由Spint1基因编码。我们之前报道过肠道特异性spint1缺失的ApcMin/+小鼠肠道肿瘤的形成加速。在本研究中，我们重点关注核因子-κB （NF-κB）信号在HAI-1缺失诱导的肿瘤易感性中的作用。在hai -1缺失的肠道中，炎症因子如肿瘤坏死因子-α和白细胞介素-6在正常粘膜中上调。此外，在hai -1缺失的ApcMin/+肠正常粘膜和肿瘤组织中均观察到NF-κB核易位增加，且NF-κB靶基因如尿激酶型纤溶酶原激活因子在hai -1缺失的肿瘤组织中上调。因此，我们研究了一种合成的NF-κB抑制剂dehydroxymethylepoxyquinomicin （DHMEQ）对肠道hai -1缺陷ApcMin/+小鼠的影响。在hai -1缺陷ApcMin/+小鼠中，与对照相比，DHMEQ治疗减少了肠道肿瘤的形成。提示HAI-1功能不足通过激活NF-κB信号通路促进肠道癌变。
Hepatocyte growth factor activator inhibitor type 1 (HAI-1), encoded by the Spint1 gene, is a membrane-bound serine protease inhibitor expressed on the epithelial cell surface. We have previously reported that the intestine-specific Spint1-deleted ApcMin/+ mice showed accelerated formation of intestinal tumors. In this study, we focused on the role of nuclear factor-κB (NF-κB) signaling in the HAI-1 loss-induced tumor susceptibility. In the HAI-1-deficient intestine, inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, were upregulated in normal mucosa. Furthermore, increased nuclear translocation of NF-κB was observed in both normal mucosa and tumor tissues of HAI-1-deficient ApcMin/+ intestines, and an NF-κB target gene, such as urokinase-type plasminogen activator, was upregulated in the HAI-1-deficient tumor tissues. Thus, we investigated the effect of dehydroxymethylepoxyquinomicin (DHMEQ), a synthetic inhibitor of NF-κB, on intestinal HAI-1-deficient ApcMin/+ mice. Treatment with DHMEQ reduced the formation of intestinal tumors compared with vehicle control in the HAI-1-deficient ApcMin/+ mice. These results suggested that insufficient HAI-1 function promotes intestinal carcinogenesis by activating NF-κB signaling.