Yun Sun-Mi, Kim Yeong Seok, Hur Dae Young
Department of Anatomy and Tumor immunology, Inje University College of Medicine, 75 Bokji-ro, Busanjin-gu, Busan 47392, Republic of Korea.
Department of Anatomy and Tumor immunology, Inje University College of Medicine, 75 Bokji-ro, Busanjin-gu, Busan 47392, Republic of Korea.
Transl Oncol. 2019 May;12(5):775-783. doi: 10.1016/j.tranon.2019.02.009. Epub 2019 Mar 22.
The transcription factor Nrf2, which regulates the expression of antioxidant and cytoprotective enzymes, contributes to cell proliferation and resistance to chemotherapy. Nrf2 is also dysregulated in many cancers such as lung, head and neck, and breast cancers, but its role in Epstein-Barr virus (EBV)-transformed B cells is still not understood. Here, we investigated EBV infection-induced Nrf2 activation in B cells by analyzing translocation of Nrf2 from the cytosol to the nucleus. In addition, we confirmed expression of the target genes in response to increased Nrf2 activation in EBV-transformed B cells. We demonstrated that knockdown of LMP1 and 2A blocks the translocation of Nrf2 to the nucleus and reduces ROS production in EBV-transformed B cells. Further, we showed that inhibition of Akt prevents Nrf2 activation. Moreover, knockdown of Nrf2 induces apoptotic cell death in EBV-transformed B cells. In conclusion, our study demonstrates that Nrf2 promotes proliferation of EBV-transformed B cells through the EBV-related proteins LMP1 and 2A and Akt signaling, implicating Nrf2 as a potential molecular target for EBV-associated disease.
转录因子Nrf2可调节抗氧化和细胞保护酶的表达，有助于细胞增殖和化疗耐药。Nrf2在许多癌症（如肺癌、头颈癌和乳腺癌）中也存在失调，但它在爱泼斯坦-巴尔病毒（EBV）转化的B细胞中的作用仍不清楚。在此，我们通过分析Nrf2从细胞质到细胞核的转位，研究了EBV感染诱导的B细胞中Nrf2的激活。此外，我们证实了EBV转化的B细胞中Nrf2激活增加时靶基因的表达。我们证明，LMP1和2A的敲低可阻断Nrf2向细胞核的转位，并减少EBV转化的B细胞中的活性氧生成。此外，我们表明抑制Akt可阻止Nrf2激活。此外，Nrf2的敲低可诱导EBV转化的B细胞发生凋亡性细胞死亡。总之，我们的研究表明，Nrf2通过EBV相关蛋白LMP1和2A以及Akt信号促进EBV转化的B细胞增殖，这表明Nrf2是EBV相关疾病的潜在分子靶点。
