Department of Respiratory and Critical Care Medicine, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, China.
Department of Clinical Laboratory, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, China.
Biochem Biophys Res Commun. 2020 Apr 16;524(4):803-809. doi: 10.1016/j.bbrc.2020.01.166. Epub 2020 Feb 7.
The carcinogenic function of arachidonate lipoxygenase12 (Alox12) has been reported in various cancers. However, little is known on the role of Alox12 in lung cancer. Here, we demonstrate that Alox12 is upregulated and contributes to biological activities of lung cancer through multiple mechanisms. We found that Alox12 mRNA and protein levels were increased by 2.5-fold in a panel of lung cancer cell lines compared to normal lung cells. The expression of Alox12 varied among lung cancer cell lines. The immunohistochemistry analysis on paired normal and tumor lung tissues from twenty patients showed that Alox12 protein level is higher in lung cancer than normal lung tissues from the majority of patients. We further observed the upregulation of Alox12-12-HETE signaling axis in lung cancer tissues. Overexpression of Alox12 promoted growth and migration in normal lung cells and lung cancer cells. In contrast, Alox12 inhibition via genetic and pharmacological approaches suppressed growth and migration, induced apoptosis, and sensitized lung cancer cells to chemotherapy. This is through suppressing RhoA signaling, inhibiting epithelial-to-mesenchymal transition (EMT) and NF-κB activity. Our work reveals the therapeutic value of inhibiting Alox12 in overcoming chemoresistance in lung cancer.
花生四烯酸脂加氧酶 12（Alox12）的致癌功能已在各种癌症中得到报道。然而，关于 Alox12 在肺癌中的作用知之甚少。在这里，我们证明 Alox12 通过多种机制上调并促进肺癌的生物学活性。我们发现，与正常肺细胞相比，在一组肺癌细胞系中，Alox12 mRNA 和蛋白水平增加了 2.5 倍。Alox12 在肺癌细胞系中的表达存在差异。对 20 名患者的配对正常和肿瘤肺组织的免疫组化分析表明，Alox12 蛋白水平在大多数患者的肺癌中高于正常肺组织。我们进一步观察到肺癌组织中 Alox12-12-HETE 信号轴的上调。Alox12 的过表达促进了正常肺细胞和肺癌细胞的生长和迁移。相比之下，通过遗传和药理学方法抑制 Alox12 抑制了生长和迁移，诱导了细胞凋亡，并使肺癌细胞对化疗敏感。这是通过抑制 RhoA 信号、抑制上皮间质转化（EMT）和 NF-κB 活性来实现的。我们的工作揭示了抑制 Alox12 在克服肺癌化疗耐药性方面的治疗价值。
