Xanthine oxidoreductase promotes the progression of colitis-associated colorectal cancer by causing DNA damage and mediating macrophage M1 polarization
Xanthine oxidoreductase promotes the progression of colitis-associated colorectal cancer by causing DNA damage and mediating macrophage M1 polarization
复制标题
DOI：
10.1016/j.ejphar.2021.174270
复制
发表时间：
2021-06-28
影响因子：
5
通讯作者：
Li, Haitao
中科院分区：
文献类型：
--
作者：
Li, Hongling;Zhang, Chengjuan;Li, Haitao
黄嘌呤氧化还原酶（Xanthine oxidoreductase，XOR）是参与超氧自由基生成的关键酶之一。氧化应激与结直肠癌的病因有关，但XOR的作用尚不清楚。在这里，我们研究了XOR在结肠炎相关性结直肠癌（CAC）中的作用及其潜在机制。使用临床样本，我们证明了XOR上调是结肠癌发生的早期事件。药物抑制XOR有效地延缓CAC的进展。此外，XOR活性与肿瘤坏死因子α（TNF α）蛋白水平呈正相关。从机制上讲，TNF α可以通过激活蛋白-1激活XOR转录，从而促进内源性过氧化氢的产生，导致结肠癌细胞中的氧化DNA损伤。另一方面，XOR可能通过介导LPS诱导的巨噬细胞M1极化来调节TNF α mRNA转录。总的来说，XOR通过编程肿瘤微环境促进肿瘤发展，并通过DNA损伤诱导的遗传不稳定性刺激CAC进展。
In addition to its pivotal role in purine metabolism, xanthine oxidoreductase (XOR) is one of the key enzymes involved in superoxide radical generation. Oxidative stress has been implicated in the etiology of colorectal cancer, but the contribution of XOR remains unclear. Here we investigated the role of XOR in colitis-associated colorectal cancer (CAC) and the underlying mechanisms. Using clinical samples, we demonstrated that XOR upregulation was an early event in colonic carcinogenesis. Pharmacological inhibition of XOR effectively delayed the progression of CAC. Moreover, XOR activity positively correlated with tumor necrosis factor-alpha (TNF alpha) protein levels. Mechanistically, TNF alpha may activate XOR transcription via activator protein-1 and, thus, promote endogenous hydrogen peroxide generation, resulting in oxidative DNA damage in colon cancer cells. On the other hand, XOR may regulate the TNF alpha mRNA transcripts by mediating LPS-induced macrophage M1 polarization. Collectively, XOR promotes tumor development by programming the tumor microenvironment and stimulates CAC progression via DNA damage-induced genetic instability.