NRSF/REST levels are decreased in cholangiocellular carcinoma but not hepatocellular carcinoma compared with normal liver tissues: A tissue microarray study

Abstract

Abstract. The transcription factor neuron-restrictive silencer factor (NRSF), also termed repressor element 1-silencing transcription factor (REST), has been previously demonstrated to repress the expression of neuronal genes in non-neuronal cells, facilitating the controlled development and organization of nerve tissue. However, previous studies have reported NRSF/REST to be upregulated or downregulated in multiple types of carcinoma. Liver diseases are a major global health concern, with cirrhosis and liver carcinoma among the most common causes of mortality worldwide. A previous study demonstrated that there were >400 NRSF/REST target genes in mouse liver cells; however, the expression profile of NRSF/REST in human liver disease remains unclear. The present study examined NRSF/REST expression in human normal and liver carcinoma samples using tissue microarray immunohistochemistry. The results demonstrated that in normal liver tissues, NRSF/REST can be detected in the cytoplasm and nuclei of the cell; whereas in the liver carcinoma tissue, NRSF/REST is only detected in the cytoplasm. Furthermore, the number of samples with high levels of NRSF/REST was significantly lower in cholangiocellular carcinoma samples compared with normal tissues. Additionally, no detectable sex-or age-associated differences were identified in NRSF/REST expression among all the tissues examined. In conclusion, the results of the present study revealed nuclear loss of NRSF/REST in hepatic carcinomas and decreased expression of NRSF/REST in cholangiocellular carcinoma, indicating that the cytoplasmic translocation of NRSF/REST may be involved in liver tumorigenesis. A low expression level of NRSF/REST may be a novel biomarker for cholangiocellular carcinoma. IntroductionNeuron-restrictive silencer factor (NRSF), also termed repressor element 1-silencing transcription factor (REST), is a zinc-finger transcription factor and an important regulator of neural genes (1). Chong et al (2) first reported that NRSF/REST is a silencer protein that reduces the expression of sodium channel genes in neurons. A previous study demonstrated that NRSF/REST is an important regulator of neurogenesis in vitro and in vivo. For example, downregulation of NRSF/REST in embryonic stem cells induces neuronal lineage differentiation (3), and knockdown of NRSF/REST in cultured neural stem cells induces the expression of pro-neuronal genes, including neuronal differentiation 1, neuron-specific class III β-tubulin and doublecortin (4). In Xenopus and chicken embryos, NRSF/REST inactivation induces abnormal neurogenesis and inhibits the repression of neuronal tubulin and several other neuronal target genes (5,6). Additionally, NRSF/REST overexpression represses the expression of neuronal genes, including N-tubulin and neuronal cell adhesion molecule (7).Numerous studies have investigated the expression and, to a lesser extent, the function of NRSF/REST in tumors of the nervous system (8-15). Certain tumors, including neuroblastoma, share a number of biological propert...

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“…In all cases, however, its main localization is in the cytoplasm, relevant for liver cancer cell proliferation. In this case, the oncogenic effect of cytoplasmic REST is paradox and not yet explained [56].…”

Computational modeling of chromatin accessibility identified important epigenomic regulators

“…REST gene was marginally studied in liver cancer. There is only a handful of studies discussing its expression and alternative splicing status in cancer [ 44 , 45 ]. Our results indicated its importance in maintaining chromatin accessibility.…”

Overexpression of ClC-3 Chloride Channel in Chondrosarcoma: An In Vivo Immunohistochemical Study with Tissue Microarray

“…After immunohistochemical staining, images were captured with a DS-Ri2 digital camera (Nikon Corporation, Tokyo, Japan) mounted to a CX41 Nikon microscope (Nikon Corporation, Tokyo, Japan). The staining was scored according to the previously described 4-point system (score 0–3) [23,24] by a pathologist (double-blinded) as follows: score 3, dark staining that is easily visible and present in >50% of cells; score 2, focal areas of dark staining (<50% of cells) or moderate staining of >50% of cells; score 1, focal moderate staining in <50% of cells or pale staining in any proportion of cells not easily observable at low power; and score 0, none of the aforementioned. A high level of expression was defined as a score of 2–3 and low level of expression was defined as a score of 0–1, as described previously.…”