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

Yu,Yanlan; Li,Shan; Zhang,Huiyan; Zhang,Xuqing; Guo,Deyu; Zhang,Jiqiang

doi:10.3892/ol.2018.8169

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

Authors:
- Yanlan Yu
- Shan Li
- Huiyan Zhang
- Xuqing Zhang
- Deyu Guo
- Jiqiang Zhang
View Affiliations

Affiliations: Department of Neurobiology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, P.R. China, Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
Published online on: March 5, 2018 https://doi.org/10.3892/ol.2018.8169
Pages: 6592-6598

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Zhao Y, Zhu M, Yu Y, Qiu L, Zhang Y, He L and Zhang J: Brain REST/NRSF is not only a silent repressor but also an active protector. Mol Neurobiol. 54:541–550. 2016. View Article : Google Scholar : PubMed/NCBI
2	Chong JA, Tapia-Ramírez J, Kim S, Toledo-Aral JJ, Zheng Y, Boutros MC, Altshuller YM, Frohman MA, Kraner SD and Mandel G: REST: A mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell. 80:949–957. 1995. View Article : Google Scholar : PubMed/NCBI
3	Gupta SK, Gressens P and Mani S: NRSF downregulation induces neuronal differentiation in mouse embryonic stem cells. Differentiation. 77:19–28. 2009. View Article : Google Scholar : PubMed/NCBI
4	Gao Z, Ure K, Ding P, Nashaat M, Yuan L, Ma J, Hammer RE and Hsieh J: The master negative regulator REST/NRSF controls adult neurogenesis by restraining the neurogenic program in quiescent stem cells. J Neurosci. 31:9772–9786. 2011. View Article : Google Scholar : PubMed/NCBI
5	Chen ZF, Paquette AJ and Anderson DJ: NRSF/REST is required in vivo for repression of multiple neuronal target genes during embryogenesis. Nat Genet. 20:136–142. 1998. View Article : Google Scholar : PubMed/NCBI
6	Olguín P, Oteíza P, Gamboa E, Gómez-Skármeta JL and Kukuljan M: RE-1 silencer of transcription/neural restrictive silencer factor modulates ectodermal patterning during Xenopus development. J Neurosci. 26:2820–2829. 2006. View Article : Google Scholar : PubMed/NCBI
7	Paquette AJ, Perez SE and Anderson DJ: Constitutive expression of the neuron-restrictive silencer factor (NRSF)/REST in differentiating neurons disrupts neuronal gene expression and causes axon pathfinding errors in vivo. Proc Natl Acad Sci USA. 97:12318–12323. 2000. View Article : Google Scholar : PubMed/NCBI
8	Nishimura E, Sasaki K, Maruyama K, Tsukada T and Yamaguchi K: Decrease in neuron-restrictive silencer factor (NRSF) mRNA levels during differentiation of cultured neuroblastoma cells. Neurosci Lett. 211:101–104. 1996. View Article : Google Scholar : PubMed/NCBI
9	Lee JH, Chai YG and Hersh LB: Expression patterns of mouse repressor element-1 silencing transcription factor 4 (REST4) and its possible function in neuroblastoma. J Mol Neurosci. 15:205–214. 2000. View Article : Google Scholar : PubMed/NCBI
10	Lepagnol-Bestel AM, Maussion G, Ramoz N, Moalic JM, Gorwood P and Simonneau M: Nrsf silencing induces molecular and subcellular changes linked to neuronal plasticity. Neuroreport. 18:441–446. 2007. View Article : Google Scholar : PubMed/NCBI
11	Lawinger P, Venugopal R, Guo ZS, Immaneni A, Sengupta D, Lu W, Rastelli L, Carneiro Marin Dias A, Levin V, Fuller GN, et al: The neuronal repressor REST/NRSF is an essential regulator in medulloblastoma cells. Nat Med. 6:826–831. 2000. View Article : Google Scholar : PubMed/NCBI
12	Su X, Gopalakrishnan V, Stearns D, Aldape K, Lang FF, Fuller G, Snyder E, Eberhart CG and Majumder S: Abnormal expression of REST/NRSF and Myc in neural stem/progenitor cells causes cerebellar tumors by blocking neuronal differentiation. Mol Cell Biol. 26:1666–1678. 2006. View Article : Google Scholar : PubMed/NCBI
13	Fuller GN, Su X, Price RE, Cohen ZR, Lang FF, Sawaya R and Majumder S: Many human medulloblastoma tumors overexpress repressor element-1 silencing transcription (REST)/neuron-restrictive silencer factor, which can be functionally countered by REST-VP16. Mol Cancer Ther. 4:343–349. 2005.PubMed/NCBI
14	Conti L, Crisafulli L, Caldera V, Tortoreto M, Brilli E, Conforti P, Zunino F, Magrassi L, Schiffer D and Cattaneo E: REST controls self-renewal and tumorigenic competence of human glioblastoma cells. PLoS One. 7:e384862012. View Article : Google Scholar : PubMed/NCBI
15	Zhang D, Li Y, Wang R, Li Y, Shi P, Kan Z and Pang X: Inhibition of rest suppresses proliferation and migration in glioblastoma cells. Int J Mol Sci. 17:pii: E664. 2016.
16	Gurrola-Diaz C, Lacroix J, Dihlmann S, Becker CM and von Knebel Doeberitz M: Reduced expression of the neuron restrictive silencer factor permits transcription of glycine receptor alpha1 subunit in small-cell lung cancer cells. Oncogene. 22:5636–5645. 2003. View Article : Google Scholar : PubMed/NCBI
17	Watanabe H, Mizutani T, Haraguchi T, Yamamichi N, Minoguchi S, Yamamichi-Nishina M, Mori N, Kameda T, Sugiyama T and Iba H: SWI/SNF complex is essential for NRSF-mediated suppression of neuronal genes in human nonsmall cell lung carcinoma cell lines. Oncogene. 25:470–479. 2006. View Article : Google Scholar : PubMed/NCBI
18	Kreisler A, Strissel PL, Strick R, Neumann SB, Schumacher U and Becker CM: Regulation of the NRSF/REST gene by methylation and CREB affects the cellular phenotype of small-cell lung cancer. Oncogene. 29:5828–5838. 2010. View Article : Google Scholar : PubMed/NCBI
19	Bronson MW, Hillenmeyer S, Park RW and Brodsky AS: Estrogen coordinates translation and transcription, revealing a role for NRSF in human breast cancer cells. Mol Endocrinol. 24:1120–1135. 2010. View Article : Google Scholar : PubMed/NCBI
20	Lv H, Pan G, Zheng G, Wu X, Ren H, Liu Y and Wen J: Expression and functions of the repressor element 1 (RE-1)-silencing transcription factor (REST) in breast cancer. J Cell Biochem. 110:968–974. 2010. View Article : Google Scholar : PubMed/NCBI
21	Varghese BV, Koohestani F, McWilliams M, Colvin A, Gunewardena S, Kinsey WH, Nowak RA, Nothnick WB and Chennathukuzhi VM: Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway. Proc Natl Acad Sci USA. 110:2187–2192. 2013. View Article : Google Scholar : PubMed/NCBI
22	Edge SB and Compton CC: The American Joint Committee on Cancer: The VIIth edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 17:1471–1474. 2010. View Article : Google Scholar : PubMed/NCBI
23	Liu M, Zhang K, Zhao Y, Guo Q, Guo D and Zhang J: Evidence for involvement of steroid receptors and coactivators in neuroepithelial and meningothelial tumors. Tumour Biol. 36:3251–3261. 2015. View Article : Google Scholar : PubMed/NCBI
24	Liu C, Zhang Y, Zhang K, Bian C, Zhao Y and Zhang J: Expression of estrogen receptors, androgen receptor and steroid receptor coactivator-3 is negatively correlated to the differentiation of astrocytic tumors. Cancer Epidemiol. 38:291–297. 2014. View Article : Google Scholar : PubMed/NCBI
25	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
26	Lu T, Aron L, Zullo J, Pan Y, Kim H, Chen Y, Yang TH, Kim HM, Drake D, Liu XS, et al: REST and stress resistance in ageing and Alzheimer's disease. Nature. 507:448–454. 2014. View Article : Google Scholar : PubMed/NCBI
27	Orta-Salazar E, Aguilar-Vázquez A, Martínez-Coria H, Luquín-De Anda S, Rivera-Cervantes M, Beas-Zarate C, Feria-Velasco A and Díaz-Cintra S: REST/NRSF-induced changes of ChAT protein expression in the neocortex and hippocampus of the 3xTg-AD mouse model for Alzheimer's disease. Life Sci. 116:83–89. 2014. View Article : Google Scholar : PubMed/NCBI
28	Majumder S: REST in good times and bad: Roles in tumor suppressor and oncogenic activities. Cell Cycle. 5:1929–1935. 2006. View Article : Google Scholar : PubMed/NCBI
29	Westbrook TF, Martin ES, Schlabach MR, Leng Y, Liang AC, Feng B, Zhao JJ, Roberts TM, Mandel G, Hannon GJ, et al: A genetic screen for candidate tumor suppressors identifies REST. Cell. 121:837–848. 2005. View Article : Google Scholar : PubMed/NCBI
30	Blom T, Tynninen O, Puputti M, Halonen M, Paetau A, Haapasalo H, Tanner M and Nupponen NN: Molecular genetic analysis of the REST/NRSF gene in nervous system tumors. Acta Neuropathol. 112:483–490. 2006. View Article : Google Scholar : PubMed/NCBI
31	Wagoner MP, Gunsalus KT, Schoenike B, Richardson AL, Friedl A and Roopra A: The transcription factor REST is lost in aggressive breast cancer. PLoS Genet. 6:e10009792010. View Article : Google Scholar : PubMed/NCBI
32	Hansel MC, Davila JC, Vosough M, Gramignoli R, Skvorak KJ, Dorko K, Marongiu F, Blake W and Strom SC: The use of induced pluripotent stem cells for the study and treatment of liver diseases. Curr Protoc Toxicol. 67:14.13.1–14.13.27. 2016. View Article : Google Scholar
33	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
34	Sedaghat Y, Bui HH, Mazur C and Monia BP: Identification of REST-regulated genes and pathways using a REST-targeted antisense approach. Nucleic Acid Ther. 23:389–400. 2013. View Article : Google Scholar : PubMed/NCBI