Department of Biochemistry and Molecular Biology, Medical Science and Engineering Research Center for Bioreaction to Reactive Oxygen Species, Biomedical Science Institute, School of Medicine, Kyung Hee University, #1 Hoegi-dong, Dongdaemoon-gu, Seoul, 130-701, Korea.
Apoptosis. 2012 Aug;17(8):784-96. doi: 10.1007/s10495-012-0730-5.
Cyclophilin, a cytosolic receptor for the immunosuppressive drug cyclosporin A, plays a role in diverse pathophysiologies along with its receptor, CD147. Although the interaction between cyclophilin A and CD147 is well established in inflammatory disease, that of cyclophilin B (CypB) with CD147 has not been fully explored, especially in cancer cell biology, and the exact molecular mechanism underlying such an association is poorly understood. In this study, we first identified high expression levels of CypB in 54 % of hepatocellular carcinoma patient tissues but in only 12.5 % of normal liver tissues. Then, we demonstrated that CypB overexpression protects human hepatoma cells against oxidative stress through its binding to CD147; this protective effect depends on the peptidyl prolyl isomerase activity of CypB. siRNA-mediated knockdown of CypB expression rendered hepatoma cells more vulnerable to ROS-mediated apoptosis. Furthermore, we also determined that a direct interaction between secreted CypB and CD147 regulates the extracellular signal-regulated kinase intracellular signaling pathway and is indispensible for the protective functions of CypB. For the first time, we demonstrated that CypB has an essential function in protecting hepatoma cells against oxidative stress through binding to CD147 and regulating the ERK pathway.
亲环素是一种细胞溶质受体，可与免疫抑制剂环孢素 A 结合，在多种病理生理过程中发挥作用，其受体为 CD147。虽然亲环素 A 与 CD147 的相互作用在炎症性疾病中已得到充分证实，但亲环素 B（CypB）与 CD147 的相互作用尚未得到充分研究，尤其是在癌细胞生物学中，这种关联的确切分子机制仍知之甚少。在这项研究中，我们首先在 54%的肝癌患者组织中鉴定到 CypB 的高表达水平，但在 12.5%的正常肝组织中仅鉴定到 CypB 的低表达水平。然后，我们证明 CypB 过表达通过与 CD147 结合来保护人肝癌细胞免受氧化应激；这种保护作用依赖于 CypB 的肽基脯氨酰顺反异构酶活性。CypB 表达的 siRNA 介导敲低使肝癌细胞更容易受到 ROS 介导的凋亡。此外，我们还确定了分泌型 CypB 与 CD147 之间的直接相互作用调节细胞外信号调节激酶细胞内信号通路，对于 CypB 的保护功能是不可或缺的。我们首次证明，CypB 通过与 CD147 结合并调节 ERK 通路，在保护肝癌细胞免受氧化应激方面发挥着重要作用。
