5-轻甲基胞嘧啶和TET家族氧合酶在肝细胞癌中的表达及临床意义

The expression and clinical significance of 5-hmC and TETs in hepatocellular carcinoma

目的探讨5-轻甲基胞嘧啶(5-hydroxymethylcytosine,5-hmC)和TET家族氧合酶(teneleven translocation protein, TET1 /2/3 )在肝细胞癌(hepatocellular carcinoma, HCC )中的表达水平和临床意义。方法采用免疫组化方法检测130例HCC组织中5-hmC的表达水平,应用Kaplan-Meier检验进行生存分析。5-hmC可以被TET1/2/3转化5-甲基胞嘧啶(5-methylcytosine,5-mC)产生,应用免疫组织化学和RT-PCR的方法分析TET1/2/3的表达变化。结果5-hmC在HCC组织中表达水平特异性的降低,同时伴有TET1表达水平的降低,TET2和TET3的表达水平无变化。5-hmC的表达水平与患者的病理学分级具有相关性(χ^2= 10.611,P = 0. 001),对患者的生存时间进行分析发现5-hmC弱阳性表达的患者生存时间明显低于5-hmC强阳性表达的患者(χ^2=4.412,P = 0. 036)。结论HCC组织中5-hmC的表达水平特异性降低,与患者的病理学分级和生存时间有相关性,TET1蛋白表达水平的降低可能是调控5-hmC的直接因素。

Objective To investigate the levels of 5-hydroxymethylcytosine ( 5-hmC) and ten- eleven-translocation proteins (TET 1/2/3 ) in diagnosis and prognosis prediction of hepatocellular carcinoma (HCC). Methods The expression of 5-hmC in 130 cases of HCC tissues were detected by immunohistochemical staining. Kaplan-Meier test was used for survival analysis. TET family plays critical role in the conversion of 5-methylcytosine ( 5-mC) to 5-hmC. The TET levels were detected by using immunohistochemical staining and RT-PCR, the correlation between 5-hmC and TET was analyzed. Results The level of 5-hmC decreased in HCC tissues, as compared with non-tumor tissues, the expression of TET1 was downregulated in HCC. There was significant difference in the expression between low and high grades of HCC tissues ( χ^2= 10.611 , P = 0. 001 ). Kaplan-Meier survival analysis showed that there was significant difference between the 5-hmC expression level and the survival rate of HCC patients ( χ^2 = 4. 412, P = 0. 036). Conclusions In HCC tissues the expression of 5-hmC was specifically downregulated. Low 5-hmC level is significantly correlated with poor differentiation of the tumor and worse overall survival. Decreased expression of TET1 is likely one of the mechanisms underlying 5-hmC loss in HCC.