Celecoxib Inhibits Hepatocellular Carcinoma Cell Growth and Migration by Targeting PNO1
Celecoxib Inhibits Hepatocellular Carcinoma Cell Growth and Migration by Targeting PNO1
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塞来昔布通过靶向 PNO1 抑制肝细胞癌细胞生长和迁移
DOI：
10.12659/msm.919218
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发表时间：
2019-09-30
影响因子：
3.1
通讯作者：
Pan, Linghui
中科院分区：
文献类型：
--
作者：
Dai, Huijun;Zhang, Suisui;Pan, Linghui
塞来昔布已显示出对几种癌症的抗肿瘤活性。尽管大多数研究都集中在其通过环氧化酶-2 （COX-2）酶抑制的机制上，但我们发现了塞来昔布抗癌能力背后的独特机制。材料/方法用塞来昔布治疗肝细胞癌（HCC） Huh-7细胞和肿瘤异种移植小鼠模型，观察其对肿瘤的影响。利用基因芯片法鉴定塞来昔布处理后的差异表达基因，并利用途径富集分析预测潜在通路，供进一步研究。我们用慢病毒shRNA转染细胞，检测NOB1 RNA结合基因伴侣（PNO1）对肿瘤生长的体外和体内影响。western blot检测PNO1对蛋白激酶B （AKT）通路的影响。结果塞来昔布在体外和体内均能抑制HCC细胞的生长，基因芯片和通路富集分析显示PNO1可能是塞来昔布在HCC细胞中的潜在靶点。塞来昔布显著降低肿瘤组织中PNO1水平。PNO1基因敲低可显著抑制肿瘤生长和体内转移。PNO1表达的破坏可显著降低蛋白激酶B (AKT)/雷帕霉素（mTOR）信号通路，表明该通路可能参与PNO1介导的致瘤活性。结论塞来昔布可能通过抑制PNO1发挥其抗肿瘤作用，AKT/mTOR信号通路参与了PNO1的致瘤作用。本研究首次证实了PNO1作为HCC癌基因的作用，这可能为HCC的预防和治疗开辟新的途径。
Background Celecoxib has shown anti-tumor activities against several types of cancer. Although the majority of research focuses on its mechanism via cyclooxygenase-2 (COX-2) enzyme inhibition, we identified a distinct mechanism behind celecoxib anti-cancer abilities. Material/Methods We treated hepatocellular carcinoma (HCC) Huh-7 cells and tumor xenograft mice models with celecoxib to test its effects on the tumor. Using gene chip method to identify the differential expressed genes after celecoxib treatment and using pathway enrichment analysis to predict the potential pathways for further study. We transfected cells with lentiviral shRNA to detect the effect of RNA binding gene partner of NOB1 (PNO1) on tumor growth in vitro and in vivo. Further we performed western blot to detect the effect of PNO1 on the protein kinase B (AKT) pathway. Results Celecoxib inhibited HCC cell growth in vitro and in vivo, and gene chip and pathway enrichment analysis revealed that PNO1 may be the potential target of celecoxib in HCC cells. Celecoxib significantly reduced levels of PNO1 in tumor tissue. Knockdown of PNO1 remarkably suppressed tumor growth and metastasis in vitro and in vivo. Disruption of PNO1 expression significantly reduced protein kinase B (AKT)/rapamycin (mTOR) signaling, indicating that this pathway may be involved in PNO1-mediated tumorigenic activity. Conclusions Celecoxib may exert its anti-tumor activity by inhibiting PNO1, and that AKT/mTOR signaling helps mediate the oncogenic effects of PNO1. This work offers the first evidence for a role of PNO1 as an HCC oncogene, which may open new avenues for prevention and treatment of HCC.