Epigenetic silencing of TMEM176A activates ERK signaling in human hepatocellular carcinoma.
Epigenetic silencing of TMEM176A activates ERK signaling in human hepatocellular carcinoma.
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TMEM176A 的表观遗传沉默激活人肝细胞癌中的 ERK 信号传导
DOI：
10.1186/s13148-018-0570-4
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发表时间：
2018-11-06
影响因子：
5.7
通讯作者：
Guo M
中科院分区：
文献类型：
--
作者：
Li H;Zhang M;Linghu E;Zhou F;Herman JG;Hu L;Guo M
背景TMEM176A在人肝细胞癌（HCC）中的作用尚不清楚。本研究探讨了TMEM176A在人肝癌中的表观遗传调控及其功能。材料与方法对12株肝癌细胞株和126例原发性肝癌进行分析。采用甲基化特异性PCR、免疫组织化学、流式细胞术和异种移植小鼠模型。结果stmem176a在SNU387、SNU182、Huh1和SNU475细胞中高表达；HepG2和PLC/PRF/5细胞表达减少；在SNU449、HBXF344、SMMC7721、Huh7、LM3细胞中均无表达。在SNU387、SNU182、Huh1和SNU475细胞中检测到TMEM176A启动子的非甲基化；HepG2和PLC/PRF/5细胞部分甲基化；在SNU449、HBXF344、SMMC7721、Huh7和LM3细胞中发现了完全甲基化。5- aza -2-脱氧胞苷处理后，在SNU449、HBXF344、SMMC7721、Huh7和LM3细胞中检测到TMEM176A的重新表达；HepG2和PLC/PRF/5细胞中TMEM176A表达增加；而在SNU387、SNU182、Huh1和SNU475细胞中均未发现表达变化。TMEM176A启动子区在75.4%（95/126）的原发性人HCC中甲基化。TMEM176A表达降低与启动子区甲基化相关（P< 0.05）。TMEM176A启动子甲基化与年龄、性别、HBV感染、肝硬化、肿瘤大小、淋巴结转移、血管癌栓塞、病变数量、TNM分期无相关性（p < 0.05）。这些结果表明TMEM176A的表达受启动子区域甲基化的调控。TMEM176A启动子甲基化与肿瘤细胞分化显著相关（P< 0.05），是3年总生存率差的独立预后因素（OS，P< 0.05）。TMEM176A表达诱导细胞凋亡；抑制细胞增殖、迁移和侵袭；抑制小鼠肝癌细胞异种移植物生长；并抑制HCC细胞中的ERK信号。结论TMEM176A启动子区在人肝癌中经常发生甲基化，TMEM176A的表达受启动子区甲基化的调控。TMEM176A启动子的甲基化可以作为HCC的诊断和预后指标。TMEM176A通过抑制ERK信号通路抑制HCC生长。
BackgroundThe role of TMEM176A in human hepatocellular carcinoma (HCC) is unknown. This study explored the epigenetic regulation and function of TMEM176A in human HCC.Materials and methodsTwelve HCC cell lines and 126 cases of primary cancer were analyzed. Methylation-specific PCR, immunohistochemistry, flow cytometry, and xenograft mouse models were employed.ResultsTMEM176A was highly expressed in SNU387, SNU182, Huh1, and SNU475 cells; reduced expression was observed in HepG2 and PLC/PRF/5 cells; and no expression was found in SNU449, HBXF344, SMMC7721, Huh7, and LM3 cells. Unmethylation of the TMEM176A promoter was detected in SNU387, SNU182, Huh1, and SNU475 cells; partial methylation was observed in HepG2 and PLC/PRF/5 cells; and complete methylation was found in SNU449, HBXF344, SMMC7721, Huh7, and LM3 cells. Upon treatment with 5-Aza-2-deoxycytidine, re-expression of TMEM176A was detected in SNU449, HBXF344, SMMC7721, Huh7, and LM3 cells; increased expression of TMEM176A was observed in HepG2 and PLC/PRF/5 cells; and no expression changes were found in SNU387, SNU182, Huh1, and SNU475 cells. The TMEM176A promoter region was methylated in 75.4% (95/126) of primary human HCC. Reduced expression of TMEM176A was associated with promoter region methylation (P< 0.05). No association was found between TMEM176A promoter methylation and age, gender, HBV infection, liver cirrhosis, tumor size, lymph node metastasis, vessel cancerous embolus, number of lesions, and TNM stage (allP> 0.05). These results demonstrated that the expression of TMEM176A is regulated by promoter region methylation. Methylation of the TMEM176A promoter was significantly associated with tumor cell differentiation (P< 0.05) and was an independent prognostic factor for poor 3-year overall survival (OS,P< 0.05). TMEM176A expression induced cell apoptosis; inhibited cell proliferation, migration, and invasion; suppressed human HCC cell xenograft growth in mice; and inhibited ERK signaling in HCC cells.ConclusionThe promoter region of TMEM176A is frequently methylated in human HCC, and the expression of TMEM176A is regulated by promoter region methylation. Methylation of the TMEM176A promoter may serve as a diagnostic and prognostic marker in HCC. TMEM176A suppresses HCC growth by inhibiting the ERK signaling pathway.
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影响因子：
4.6
作者：
Drujont L;Lemoine A;Moreau A;Bienvenu G;Lancien M;Cens T;Guillot F;Bériou G;Bouchet-Delbos L;Fehling HJ;Chiffoleau E;Nicot AB;Charnet P;Martin JC;Josien R;Cuturi MC;Louvet C
通讯作者：
Louvet C
影响因子：
3.2
作者：
Liang, YH;Buckley, TR;Tedder, TF
通讯作者：
Tedder, TF
DOI：
10.1165/ajrcmb.20.2.3368
发表时间：
1999-02-01
影响因子：
6.4
作者：
Lurton, J;Rose, TM;Narayanan, AS
通讯作者：
Narayanan, AS
影响因子：
3.4
作者：
Kimmel, Robert R.;Zhao, Lue Ping;Neiman, Paul E.
通讯作者：
Neiman, Paul E.
影响因子：
4.4
作者：
Wang, Y;Han, KJ;Chen, WF
通讯作者：
Chen, WF