Deletions of chromosome 17p, where TP53 gene locates, are the most frequent chromosome alterations in human cancers and associated with poor outcomes in patients. Our previous work suggested that there were p53–independent mechanisms involved in chromosome 17p deletions-driven cancers. Here, we report that altered arachidonate metabolism, due to the deficiency of mouse Alox8 on chromosome 11B3 (homologous to human ALOX15B on chromosome 17p), contributes to the B cell malignancy. While the metabolites produced from lipoxygenase pathway reduced, chromosome 11B3 deletions or Alox8 loss, lead to upregulating its paralleling cyclooxygenase pathway, indicated by the increased levels of oncometabolite prostaglandin E2. Ectopic PGE2 prevented the apoptosis and differentiation of pre-B cells. Further studies revealed that Alox8 deficiency dramatically and specifically induced Cox-2(Ptgs2) gene expression. Repressing Cox-2 by its shRNAs impaired the tumorigenesis driven by Alox8 loss. And, in turn, tumor cells with Alox8 or 11B3 loss were sensitive to the COX-2 inhibitor celecoxib. This correlation between COX-2 upregulation and chromosome 17p deletions was consistent in human B-cell lymphomas. Hence, our studies reveal that the arachidonate metabolism abnormality with unbalanced ALOX and COX pathways underlies human cancers with 17p deletions and suggest new susceptibility for this disease.

TP53基因所在的 17p 号染色体缺失是人类癌症中最常见的染色体改变，与患者的不良预后相关。我们之前的工作表明，染色体 17p 缺失驱动的癌症涉及p53独立机制。在这里，我们报告说，由于小鼠11B3 号染色体上的Alox8 （与染色体 17p 上的人类ALOX15B同源）的缺陷，花生四烯酸代谢发生改变，导致 B 细胞恶性肿瘤。虽然脂氧合酶途径产生的代谢物减少，但染色体 11B3 缺失或Alox8损失，导致上调其平行的环氧合酶途径，表现为癌代谢物前列腺素 E2 水平升高。异位 PGE2 阻止了前 B 细胞的凋亡和分化。进一步的研究表明，Alox8缺陷显着且特异性地诱导Cox-2(Ptgs2)基因表达。通过其 shRNA抑制Cox-2会损害由Alox8缺失驱动的肿瘤发生。反过来，带有Alox8 的肿瘤细胞或 11B3 丢失对 COX-2 抑制剂塞来昔布敏感。COX-2 上调与染色体 17p 缺失之间的这种相关性在人类 B 细胞淋巴瘤中是一致的。因此，我们的研究表明，ALOX 和 COX 通路不平衡的花生四烯酸代谢异常是人类癌症 17p 缺失的基础，并表明该疾病具有新的易感性。