MST4通过激活MAPK-ERK信号通路调节炎症因子释放促进肝癌的侵袭和转移的机制研究

doi:10.19401/j.cnki.1007-3639.2017.09.001

中国癌症杂志 ›› 2017, Vol. 27 ›› Issue (9): 681-686.doi: 10.19401/j.cnki.1007-3639.2017.09.001

MST4通过激活MAPK-ERK信号通路调节炎症因子释放促进肝癌的侵袭和转移的机制研究

林镇海¹，闫士灿²，张洁筠³，王　鲁¹，潘　奇¹

1. 复旦大学附属肿瘤医院肝脏外科，复旦大学上海医学院肿瘤学系，上海 200032 ；
2. 复旦大学附属华山医院普通外科，上海 200040 ；
3. 复旦大学附属肿瘤医院肿瘤内科，复旦大学上海医学院肿瘤学系，上海 200032

出版日期:2017-09-30 发布日期:2017-09-27
通信作者: 潘　奇　E-mail：drpanqi@163.com
基金资助:
国家自然科学基金青年项目(81602100)；上海市自然科学基金面上项目(12ZR1406200)；复旦大学附属肿瘤医院院级基金(2015-2017)。

MST4 upregulates secretion of inflammatory factors via activation of MAPK-ERK signaling pathway and promotes invasion and metastasis of hepatocellular carcinoma

LIN Zhenhai¹, YAN Shican², ZHANG Jieyun³, WANG Lu¹, PAN Qi¹

1. Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; 2. Department of General Surgery, Huashan Hospital of Fudan University, Shanghai 200040, China; 3. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China

Published:2017-09-30 Online:2017-09-27
Contact: PAN Qi E-mail: drpanqi@163.com

摘要/Abstract

摘要： 背景与目的：丝氨酸/苏氨酸蛋白激酶4(mammalian Ste20-like kinase 4，MST4)促进肿瘤的侵袭和转移，前期研究发现，MST4可以通过上皮间质转化促进肝癌细胞的侵袭和转移。该研究旨在探讨MST4通过激活丝裂原活化蛋白激酶信号通路-细胞外信号调节激酶(mitogen-activated protein kinaseextracellular signal-regulated kinase，MAPK-ERK)信号通路影响炎症因子释放调节炎症微环境，促进肝癌的侵袭和转移。方法：采用实时荧光定量聚合酶链反应(real-time fluorescent quantitative polymerase chain reaction，RTFQ-PCR)方法对MST4高表达的肝癌细胞中白介素1β(interleukin-1β，IL-1β)、白介素6(interleukin-6，IL-6)、肿瘤坏死因子α(tumor necrosis factor-α，TNF-α)和趋化因子2(CC chemokine ligand-2，CCL2)的转录水平进行检查，通过蛋白［质］印迹法(Western blot)和酶联免疫吸附测定法(enzyme-linked immune sorbent assay，ELISA)研究MST4对肝癌细胞分泌炎症因子IL-1β、IL-6、TNF-α和CCL2蛋白量的表达及活性的影响。结果：MST4高表达的肝癌细胞，其IL-1β、IL-6、TNF-α和CCL2的转录水平、蛋白水平和分泌水平显著高于MST4低表达的肝癌细胞系(P＜0.05)。同时发现MST4可以通过改变ERK磷酸化的水平，促进细胞因子释放的改变。结论：MST4可以通过MAPK-ERK信号通路活化完成对肿瘤细胞分泌炎症因子的调节，促进炎症因子的分泌，增强肝癌细胞侵袭和转移的能力。

关键词: 丝氨酸/苏氨酸蛋白激酶4, 肝癌, 炎症因子, 侵袭和转移

Abstract: Background and purpose: It has been reported that mammalian Ste20-like kinase 4 (MST4) promotes the invasion and metastasis of tumors. In the previous research, we found that MST4 promoted invasion and metastasis of liver cancer through epithelial-mesenchymal transition. In this study, we explored the effect of MST4 on promoting the invasion and metastasis of hepatocellular carcinoma (HCC) cells by activating MAPK-ERK signaling pathway and inflammatory factors. Methods: We used real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) to detect the transcription of IL-1β, IL-6, TNF-α and CCL2 in different HCC cell lines expressing MST4 differently. Then we studied the different secretion of IL-1β, IL-6, TNF-α and CCL2 in cells using Western blot and enzyme-linked immunosorbent assay (ELISA). Results: The RNA transcription and protein translation levels of IL-1β, IL-6, TNF-α and CCL2 were significantly higher in HCC cell line with high expression of MST4 than those in the HCC cell line with lower expression of MST4 (P<0.05). We found that MST4 could change the level of phosphorylation of ERK to promote secretion of inflammatory cytokines. Conclusion: High expression of MST4 can upregulate the secretion of inflammatory factors (IL-1β, IL-6, TNF-α and CCL2) in HCC cells and enhance the ability of invasion and metastasis of HCC cells, through activating the MAPK-ERK signaling pathway.

Key words: Mammalian Ste20-like kinase 4, Hepatocellular carcinoma, Inflammatory factors, Invasion and metastasis

林镇海,闫士灿,张洁筠,等. MST4通过激活MAPK-ERK信号通路调节炎症因子释放促进肝癌的侵袭和转移的机制研究[J]. 中国癌症杂志, 2017, 27(9): 681-686.

LIN Zhenhai, YAN Shican, ZHANG Jieyun, et al. MST4 upregulates secretion of inflammatory factors via activation of MAPK-ERK signaling pathway and promotes invasion and metastasis of hepatocellular carcinoma[J]. China Oncology, 2017, 27(9): 681-686.

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MST4通过激活MAPK-ERK信号通路调节炎症因子释放促进肝癌的侵袭和转移的机制研究

MST4 upregulates secretion of inflammatory factors via activation of MAPK-ERK signaling pathway and promotes invasion and metastasis of hepatocellular carcinoma

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