Interleukin-8 (IL-8) is a pro-inflammatory chemokine that is associated with induction of chemotaxis and degranulation of neutrophils. IL-8 is overexpressed in many tumors, including colon and lung cancer, and recent studies demonstrated essential roles for IL-8 in tumor progression within the tumor microenvironment. However, the molecular mechanism underlying the functions of IL-8 in tumor progression is unclear. In this study, we found that IL-8 is overexpressed in colon and lung cancer cells with cancer stem cell (CSC)-like characteristics and is required for CSC properties, including tumor-initiating abilities. These findings suggest that IL-8 plays an essential role in the development of CSCs. We also showed that IL-8 stimulation of colon and lung cancer cells-induced glucose uptake and expressions of glucose transporter 3 (GLUT3) and glucosamine fructose-6-phosphate aminotransferase (GFAT), a regulator of glucose flux to the hexosamine biosynthetic pathway, resulting in enhancement of protein O-GlcNAcylation. We demonstrated that these events are required for the generation and maintenance CSC-like characteristics of colon and lung cancer cells. Moreover, an O-GlcNAcylation inhibitor, OSMI1, reduced CSC number and tumor development in vivo. Together, these results reveal that IL-8-induced O-GlcNAcylation is required for generation and maintenance of CSCs of colon and lung cancer cells and suggests this regulatory pathway as a candidate therapeutic target of CSCs.

中文翻译：

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IL-8通过GLUT3和GFAT诱导的O-GlcNAc修饰可调节结肠和肺癌细胞中的癌症干细胞样特性。

白介素8（IL-8）是一种促炎性趋化因子，与嗜中性粒细胞的趋化性和脱粒有关。IL-8在包括结肠癌和肺癌在内的许多肿瘤中均过表达，最近的研究表明IL-8在肿瘤微环境中的肿瘤进展中起着至关重要的作用。然而，尚不清楚IL-8在肿瘤进展中的功能的分子机制。在这项研究中，我们发现IL-8在具有癌干细胞（CSC）类特征的结肠和肺癌细胞中过表达，并且CSC特性（包括肿瘤引发能力）也需要IL-8。这些发现表明IL-8在CSC的发展中起着至关重要的作用。我们还显示，IL-8刺激结肠癌和肺癌细胞诱导的葡萄糖摄取以及葡萄糖转运蛋白3（GLUT3）和葡萄糖胺果糖6磷酸氨基转移酶（GFAT）（对六胺生物合成途径的葡萄糖通量的调节剂）的表达，导致蛋白O-GlcNAcylation增强。我们证明了这些事件是结肠和肺癌细胞的产生和维持CSC样特征所必需的。此外，O-GlcNAcylation抑制剂OSMI1可降低体内CSC数量和肿瘤发展。总之，这些结果表明，IL-8诱导的O-GlcNAcylation是结肠癌和肺癌细胞CSC的产生和维持所必需的，并表明该调节途径是CSC的候选治疗靶点。葡萄糖到六胺生物合成途径的调节剂，导致蛋白质O-GlcNAcylation的增强。我们证明了这些事件是结肠和肺癌细胞的产生和维持CSC样特征所必需的。此外，O-GlcNAcylation抑制剂OSMI1可降低体内CSC数量和肿瘤发展。总之，这些结果表明，IL-8诱导的O-GlcNAcylation是结肠癌和肺癌细胞CSC的产生和维持所必需的，并表明该调节途径是CSC的候选治疗靶点。葡萄糖到六胺生物合成途径的调节剂，导致蛋白质O-GlcNAcylation的增强。我们证明了这些事件是结肠和肺癌细胞的生成和维持CSC样特征所必需的。此外，O-GlcNAcylation抑制剂OSMI1可降低体内的CSC数量和肿瘤发展。总之，这些结果表明，IL-8诱导的O-GlcNAcylation是结肠癌和肺癌细胞CSC的产生和维持所必需的，并表明该调节途径是CSC的候选治疗靶点。OSMI1可减少体内的CSC数量和肿瘤发展。总之，这些结果表明，IL-8诱导的O-GlcNAcylation是结肠癌和肺癌细胞CSC的产生和维持所必需的，并表明该调节途径是CSC的候选治疗靶点。OSMI1可减少体内的CSC数量和肿瘤发展。总之，这些结果表明，IL-8诱导的O-GlcNAcylation是结肠癌和肺癌细胞CSC的产生和维持所必需的，并表明该调节途径是CSC的候选治疗靶点。