Metallothionein expression in colorectal cancer: relevance of different isoforms for tumor progression and patient survival
Metallothionein expression in colorectal cancer: relevance of different isoforms for tumor progression and patient survival
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DOI：
10.1016/j.humpath.2011.04.015
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发表时间：
2012-02-01
期刊：
影响因子：
3.3
通讯作者：
Bianchini, Michele
中科院分区：
文献类型：
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作者：
Martin Arriaga, Juan;Mariel Levy, Estrella;Bianchini, Michele
金属硫蛋白是一类小的富含半胱氨酸的蛋白，具有多种功能。与正常组织相比，结直肠肿瘤中所有金属硫蛋白1 + 2亚型的免疫组化评价显示其显著下调，但其预后意义尚不清楚。此外，个体异构体对金属硫蛋白整体下调的贡献尚不清楚。为了解决这些重要问题，我们通过定量逆转录聚合酶链反应分析了22对正常和肿瘤微解剖上皮细胞中所有功能性金属硫蛋白1 + 2亚型的信使RNA表达水平，并将其与整体免疫组织化学蛋白表达相关联。我们的研究结果显示，在从正常粘膜到肿瘤的转变过程中，有5种异构体（MT1G、1E、1F、1H和1M）丢失，而MT1X和MT2A的下调较少，其表达与总蛋白阳性相关。其次，我们发现MT1G高甲基化发生在细胞系和29%的肿瘤样本中，而组蛋白去乙酰化酶抑制剂能够诱导大多数亚型。此外，我们通过免疫组织化学分析了107例正常粘膜、25例腺瘤、81例癌和19例淋巴结转移瘤，以评估金属硫蛋白在不同癌症发展阶段的表达，并评估其与患者生存的关系。较低的免疫组织化学表达与较差的生存率相关，尽管它不是一个独立的预测因子。总体而言，本研究首次确定了与结直肠癌进展相关的金属硫蛋白亚型，支持其缺失与预后不良相关的概念，并提出了金属硫蛋白在结直肠癌中表达的两种表观遗传抑制机制。(C) 2012爱思唯尔公司版权所有。
Metallothioneins are a family of small, cysteine-rich proteins with many functions. Immunohistochemical evaluation of all metallothionein 1 + 2 isoforms in colorectal tumors has demonstrated an important down-regulation compared with normal tissue, although its prognostic significance is unclear. Moreover, the contribution of individual isoforms to overall metallothionein down-regulation is not known. To address these important issues, we analyzed the messenger RNA expression levels of all functional metallothionein 1 + 2 isoforms by quantitative reverse transcription polymerase chain reaction in 22 pairs of normal and tumor-microdissected epithelia and correlated these to the overall immunohistochemical protein expression. Our results showed that 5 isoforms (MT1G, 1E, 1F, 1H, and 1M) were lost during the transition from normal mucosa to tumor, whereas MT1X and MT2A were less down-regulated, and their expression was correlated with overall protein positivity. Second, we showed that MT1G hypermethylation occurred in cell lines and in 29% of tumor samples, whereas histone deacetylase inhibitors are able to induce most isoforms. Furthermore, we analyzed by immunohistochemistry 107 normal mucosae, 25 adenomas, 81 carcinomas, and 19 lymph node metastases to evaluate metallothionein expression during different stages of cancer development and to assess its relationship to patient survival. A lower immunohistochemical expression was associated with poorer survival, although it was not an independent predictor. Overall, this study identifies for the first time the relevant metallothionein isoforms for colorectal cancer progression, supports the concept that their loss is associated with worse prognosis, and suggests 2 mechanisms for epigenetic repression of metallothionein expression in colorectal tumors. (C) 2012 Elsevier Inc. All rights reserved.