Ding Ran-Ran, Yuan Jian-Ling, Jia Ya-Nan, Liao Xiao-Min, Wang Si-Si, Shao Zhong-Ming, Feng Mu-Yin, Jie Wei, Shen Zhi-Hua
Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Pathology, School of Basic Medicine Sciences, Guangdong Medical University, Zhanjiang 524023, China,
Onco Targets Ther. 2019 Feb 11;12:1137-1146. doi: 10.2147/OTT.S190274. eCollection 2019.
Epstein-Barr virus-encoded LMP1 plays a critical role in the carcinogenesis of nasopharyngeal carcinoma (NPC), but the mechanism remains elusive. We aimed to analyze the expression and clinical pathological significance of provirus integration site for Moloney murine leukemia virus 1 (Pim1) in clinical NPC, and to elucidate the effect of LMP1 on Pim1 expression and its mechanism.
Immunohistochemical staining was used to detect the expression of Pim1 in clinical NPC tissues and control nasopharyngeal chronic inflammation (NPI) tissues, and the correlation between Pim1 and clinical parameters of NPC patients was analyzed. The LMP1 stable expression cell line CNE1-LMP1-OV was constructed through infecting the well-differentiated nasopharyngeal carcinoma cells CNE1 with LMP1 overexpressing lentivirus. Then the in vivo experiments were conducted.
Among 89 NPC patients, 48 cases (53.93%) were positive for Pim1, while only one case was Pim1 positive in 15 NPI controls (6.67%). Pim1 expression was not correlated with gender, age, smoking status and clinical classification of NPC patients, but positively correlated with T, N and M classification. CNE1-LMP1-OV cell line was successfully established, which displayed a higher cell proliferation ability and Pim1 expression. NF-κB inhibitor PDTC, PKC inhibitor GF109203X and STAT3 inhibitor Stattic significantly attenuated LMP1-induced Pim1 expression, and while AP-1 inhibitor SR11302 showed no inhibitory effect. Interestingly, Pim1 inhibitor quercetagetin significantly inhibited the proliferation of CNE1-LMP1-OV cells.
LMP1 mediates Pim1 expression through NF-κB, PKC and STAT3 signaling, which promotes the proliferation of NPC cells and participate in the clinical progression of NPC.
爱泼斯坦-巴尔病毒编码的潜伏膜蛋白1（LMP1）在鼻咽癌（NPC）的致癌过程中起关键作用，但其机制仍不清楚。我们旨在分析莫洛尼鼠白血病病毒1前病毒整合位点（Pim1）在临床鼻咽癌中的表达及临床病理意义，并阐明LMP1对Pim1表达的影响及其机制。
采用免疫组织化学染色检测Pim1在临床鼻咽癌组织和对照鼻咽慢性炎症（NPI）组织中的表达，并分析Pim1与鼻咽癌患者临床参数的相关性。通过用LMP1过表达慢病毒感染高分化鼻咽癌细胞CNE1构建LMP1稳定表达细胞系CNE1-LMP1-OV。然后进行体内实验。
89例鼻咽癌患者中，48例（53.93%）Pim1阳性，而15例NPI对照中仅1例Pim1阳性（6.67%）。Pim1表达与鼻咽癌患者的性别、年龄、吸烟状况及临床分期无关，但与T、N和M分期呈正相关。成功建立了CNE1-LMP1-OV细胞系，其具有较高的细胞增殖能力和Pim1表达。NF-κB抑制剂PDTC、PKC抑制剂GF109203X和STAT3抑制剂Stattic显著减弱LMP1诱导的Pim1表达，而AP-1抑制剂SR11302无抑制作用。有趣的是，Pim1抑制剂槲皮黄素显著抑制CNE1-LMP1-OV细胞的增殖。
LMP1通过NF-κB、PKC和STAT3信号介导Pim1表达，促进鼻咽癌细胞增殖并参与鼻咽癌的临床进展。
