LCN2在宫颈癌和食管癌中高表达的机制及作用

Mechanism and Role of High-expression of LCN2 in Cervical and Esophageal Cancer

肿瘤细胞异常表达LCN2的调控机制及作用目前尚不明确。本研究通过Oncomine数据库分析发现,LCN2在宫颈癌和食管癌等多种肿瘤组织中高表达。进一步分析在TNFα处理的宫颈癌细胞内测得的NF-κB/ChIP-Seq数据发现,LCN2基因区的转录活性标记区(DNaseⅠ超敏感位点,H3K27Ac修饰标记位点和转录因子结合位点)覆盖24个富集倍数大于20的NF-κB结合峰,其中启动子区上的结合峰最高,且每个NF-κB结合峰包含许多κB位点。采用ChIP-qPCR验证了LCN2启动子区的NF-κB结合峰。15 ng/m L、30 ng/m L和60 ng/mL的TNFα以及TNFα的细胞内过表达均诱导宫颈癌细胞和食管癌细胞上调LCN2的表达,而NF-κB抑制剂(Bay11-7082和NF-κB/p65 siRNA)可阻止TNFα诱导宫颈癌细胞和食管癌细胞上调LCN2表达。以上结果表明TNFα可诱导NF-κB结合并上调LCN2。本研究还发现,LCN2高表达促进食管癌细胞和宫颈癌细胞增殖,高表达LCN2的宫颈癌患者预后不良。总之,本研究揭示了宫颈癌和食管癌中LCN2高表达的分子机制及作用。

The molecular mechanisms and roles of abnormally expression of LCN2 in cancer cells remain unclear.LCN2 were highly expressed in a variety of cancer tissues including cervical cancer and esophageal cancer analyzed by using oncomine database.Further analysis of the high-throughput data of NF-κB/ChIP-Seq measured in cervical cancer cells treated with TNFαshowed that the transcriptional activity mark regions(Including DNaseⅠClusters,layered H3 K27 Ac track and txn factor ChIP track)of LCN2 were covered with 24 NF-κB-bound peaks with fold enrichment over 20.Among them,the highest peak located at promoter region of LCN2.Each NF-κB-bound peaks contained manyκB sites.The NF-κB-bound peak in promoter region was confirmed by ChIP-qPCR assay.Treatment of TNFαwith three concentrations(15 ng/mL,30 ng/mL and 60 ng/mL)and ectopic expression plasmids of TNFαsignificantly increased expression of LCN2 in cervical cancer cells and esophageal cancer cells.NF-κB inhibitors(Bay11-7082 and NF-κB/p65 siRNA)significantly blocked the increase of LCN2 expression induced by TNFαin the cancer cells.Herein,the study have found that NF-κB up-regulated LCN2 expression in TNFα-treated cervical cancer cells and esophageal cancer cells.It was also found that overexpression of LCN2 promoted the proliferation of esophageal cancer cells and cervical cancer cells,and contributed poor prognosis of cervical cancer.In conclusion,this study revealed the molecular mechanisms and roles of overexpression of LCN2 in cervical cancer and esophageal cancer.