Wu Yuanqing, Mao Fei, Zuo Xiangsheng, Moussalli Micheline J, Elias Elias, Xu Weiguo, Shureiqi Imad
Department of Clinical Cancer, The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030.
Cancer Med. 2014 Jun;3(3):472-84. doi: 10.1002/cam4.222. Epub 2014 Mar 15.
The expression of 15-lipoxygenase-1 (15-LOX-1) is downregulated in colon cancer and other major cancers, and 15-LOX-1 reexpression in cancer cells suppresses colonic tumorigenesis. Various lines of evidence indicate that 15-LOX-1 expression suppresses premetastatic stages of colonic tumorigenesis; nevertheless, the role of 15-LOX-1 loss of expression in cancer epithelial cells in metastases continues to be debated. Hypoxia, a common feature of the cancer microenvironment, promotes prometastatic mechanisms such as the upregulation of hypoxia-inducible factor (HIF)-1α, a transcriptional master regulator that enhances cancer cell metastatic potential, angiogenesis, and tumor cell invasion and migration. We have, therefore, tested whether restoring 15-LOX-1 in colon cancer cells affects cancer cells' hypoxia response that promotes metastasis. We found that 15-LOX-1 reexpression in HCT116, HT29LMM, and LoVo colon cancer cells inhibited survival, vascular endothelial growth factor (VEGF) expression, angiogenesis, cancer cell migration and invasion, and HIF-1α protein expression and stability under hypoxia. These findings demonstrate that 15-LOX-1 expression loss in cancer cells promotes metastasis and that therapeutically targeting ubiquitous 15-LOX-1 loss in cancer cells has the potential to suppress metastasis.
15-脂氧合酶-1（15-LOX-1）在结肠癌和其他主要癌症中的表达下调，癌细胞中15-LOX-1的重新表达可抑制结肠肿瘤发生。各种证据表明，15-LOX-1的表达可抑制结肠肿瘤发生的转移前阶段；然而，15-LOX-1在癌症上皮细胞中表达缺失在转移中的作用仍存在争议。缺氧是癌症微环境的一个共同特征，它促进转移前机制，如缺氧诱导因子（HIF）-1α的上调，HIF-1α是一种转录主调节因子，可增强癌细胞的转移潜能、血管生成以及肿瘤细胞的侵袭和迁移。因此，我们测试了在结肠癌细胞中恢复15-LOX-1是否会影响促进转移的癌细胞缺氧反应。我们发现，在HCT116、HT29LMM和LoVo结肠癌细胞中重新表达15-LOX-1可抑制缺氧条件下的细胞存活、血管内皮生长因子（VEGF）表达、血管生成、癌细胞迁移和侵袭以及HIF-1α蛋白表达和稳定性。这些发现表明，癌细胞中15-LOX-1表达缺失会促进转移，针对癌细胞中普遍存在的15-LOX-1表达缺失进行治疗有可能抑制转移。
