TNF-α Promotes Cell Cycle Progression by Activating NF-κB Signal Pathway in Hepatic Cell Line L-02
投稿时间：2006-11-17 最后修改时间：2007-2-7
稿件编号：20060915
中文关键词：肿瘤坏死因子α (TNF-α)，核因子κB (NF-κB)，ERK，细胞周期，慢性炎症，肿瘤发生
英文关键词：tumor necrosis factor α, nuclear factor κB, extracellular signal-regulated kinase, cell cycle, chronic inflammation, tumorigenesis
基金项目：国家重点基础研究发展规划项目 (2004CB518805)，国家自然科学基金 (30470960 ，30371491)资助项目.
作者 单位
 杨季云 四川大学华西医院医学遗传研究室
曾祥元 成都军区总医院临床实验科
张思仲 四川大学华西医院医学遗传研究室
郭红 生物治疗国家重点实验室基因工程小鼠中心
马布仁 成都军区总医院临床实验科
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中文摘要：
在慢性炎症部位有易发肿瘤的倾向，大约有20%的恶性肿瘤发生与慢性炎症相关，肝细胞癌是世界第三大癌症死亡病因，其患者多数有慢性炎症病史，当炎症慢性迁延，肝细胞癌发生率明显增加. 但慢性炎症与肿瘤发生与发展的细胞和分子机制仍然不清楚. 利用人肝细胞株L-02细胞，研究肿瘤坏死因子α (TNF-α)对细胞周期的影响及其机制；并探讨核因子κB(NF-κB)和ERK1/2活化对细胞周期的影响. 以期能更确切地阐明炎症介质TNF-α在肝细胞癌发生发展中的作用. 发现TNF-α能促进肝细胞从G0/G1期向S期转换. 蛋白质印迹检测表明，TNF-α能以剂量依赖方式诱导cyclin D1表达，而对cyclin E的表达无明显影响. 同时TNF-α能激活NF-κB，ERK1/2，抑制NF-κB活化降低了TNF-α诱导的cyclin D1表达，导致细胞周期阻滞于G0/G1期. 抑制ERK1/2活化则对细胞周期和cyclin D1表达无显著影响. 结果提示，TNF-α通过活化NF-κB信号通路，诱导cyclin D1表达，加快细胞周期进程，这可能是促进肿瘤的发生发展重要机制. 针对TNF-α和NF-κB的治疗可能延长慢性炎症相关性肿瘤的潜伏期和抑制肿瘤的发展.
英文摘要：
A causal relationship between inflammation and cancer has long been suspected. It was demonstrated the presence of leukocytes in malignant tissues and claimed that tumors arise from regions of chronic inflammation. Hepatocellular carcinoma (HCC), the third leading cause of cancer mortality worldwide, commonly develops in the background of chronic hepatitis. The molecular and cellular mechanisms linking chronic inflammation to tumorigenesis remain largely unresolved. To investigate the roles of TNF-α on the formation and development of HCC, cell cycle, cyclin D1 and cyclin E was measured after treatment with TNF-α. Meanwhile, phosphorylated ERK1/2 and NF-κB activation were also assessed. After blocking the activation of ERK1/2 and NF-κB, the distribution of cell cycle and cyclin D1 expression was measured. It was found that G0/G1-to-S-phase transition was accelerated in human hepatic cell line L-02 treated by TNF-α treatment. Also TNF-α treatment can induce cyclin D1 expression in dose dependent but not cyclin E expression. Simultaneously, inhibition of NF-κB but not inhibition of ERK1/2 caused TNF-α-induced cell cycle arrest at G0/G1 and the increased levels of cyclin D1 expression. These result suggest that TNF-α promotes cell cycle progression by increasing expression of cyclin D1 due to NF-κB activation in human hepatic cell line L-02. Therefore, it enhances formation and progression of hepatocellular carcinoma. Suppression of a major signalling factor of inflammation, such as NF-κB or TNF-α, could thus be a tool to prolong the premalignant phase and inhibit tumour progression in chronic inflammatory diseases with high cancer risk. www.pibb.ac.cn/cn/ch/common/view_abstract.aspx?file_no=20060915&flag=1
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发表于 2007-6-2 04:45
