Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.
Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
Biochim Biophys Acta Mol Basis Dis. 2023 Jan 1;1869(1):166588. doi: 10.1016/j.bbadis.2022.166588. Epub 2022 Oct 29.
Strains of Helicobacter pylori that are positive for the oncoprotein CagA (cytotoxin-associated gene A) are associated with gastric cancer and might be related to the epithelial-to-mesenchymal transition (EMT). Casein kinase 2 (CK2) is a serine/threonine protein kinase that plays a major role in tumorigenesis through signaling pathways related to the EMT. However, the role played by the interaction between CagA and CK2 in gastric carcinogenesis is poorly understood. Although CK2α protein expression remained unchanged during H. pylori infection, we found that CK2α kinase activity was increased in gastric epithelial cells. We also found that the CK2β protein level decreased in H. pylori-infected gastric cancer cells in CagA-dependent manner and demonstrated that CagA induced CK2β degradation via HDM2 (human double minute 2; its murine equivalent is MDM2). We observed that CagA induced HDM2 protein phosphorylation and that p53 levels were decreased in H. pylori-infected gastric cancer cells. In addition, downregulation of CK2β induced AKT Ser473 phosphorylation and decreased the AKT Ser129 phosphorylation level in gastric cancer cells. We also found that the downregulation of CK2β triggered the upregulation of Snail levels in gastric cancer cells. Furthermore, our in vivo experiments and functional assays of migration and colony formation suggest that CK2β downregulation is a major factor responsible for the EMT in gastric cancer. Therefore, CK2 could be a key mediator of the EMT in H. pylori-infected gastric cancer and could serve as a molecular target for gastric cancer treatment.
细胞毒素相关基因 A（Cytotoxin-associated gene A，CagA）阳性的幽门螺杆菌菌株与胃癌相关，并且可能与上皮-间充质转化（epithelial-to-mesenchymal transition，EMT）有关。酪蛋白激酶 2（casein kinase 2，CK2）是一种丝氨酸/苏氨酸蛋白激酶，通过与 EMT 相关的信号通路在肿瘤发生中发挥主要作用。然而，CagA 与 CK2 之间的相互作用在胃癌发生中的作用尚不清楚。尽管在幽门螺杆菌感染过程中 CK2α 蛋白表达保持不变，但我们发现 CK2α 激酶活性在胃上皮细胞中增加。我们还发现，CK2β 蛋白水平在 CagA 依赖性方式下在感染幽门螺杆菌的胃癌细胞中降低，并证明 CagA 通过 HDM2（human double minute 2；其鼠类对应物是 MDM2）诱导 CK2β 降解。我们观察到 CagA 诱导 HDM2 蛋白磷酸化，并且感染幽门螺杆菌的胃癌细胞中的 p53 水平降低。此外，CK2β 的下调诱导 AKT Ser473 磷酸化并降低胃癌细胞中 AKT Ser129 的磷酸化水平。我们还发现，CK2β 的下调触发胃癌细胞中 Snail 水平的上调。此外，我们的体内实验和迁移及集落形成的功能测定表明，CK2β 的下调是胃癌 EMT 的主要因素。因此，CK2 可能是幽门螺杆菌感染的胃癌 EMT 的关键介质，并可能成为胃癌治疗的分子靶标。
