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Published in: Clinical & Experimental Metastasis 1/2015

01-01-2015

RASSF5A, a candidate tumor suppressor, is epigenetically inactivated in esophageal squamous cell carcinoma

Authors: Wei Guo, Cong Wang, Yanli Guo, Supeng Shen, Xin Guo, Gang Kuang, Zhiming Dong

Published in: Clinical & Experimental Metastasis | Issue 1/2015

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Abstract

As a result of alternative splicing and differential promoter usage, RASSF5 exists in at least three isoforms (RASSF5A–RASSF5C), which may play different roles in tumorigenesis. The present study was to detect the role of RASSF5A, B and C in esophageal squamous cell carcinoma (ESCC) and clarify the critical CpG sites of RASSF5A, in order to clarify more information on the role of RASSF5 with regard to the pathogenesis of ESCC. Frequent silencing of RASSF5A but not RASSF5B and RASSF5C were found in esophageal cancer cell lines and the silencing of RASSF5A may be reversed by 5-Aza-dC or TSA treatment. The aberrant CpG island 1 methylation of RASSF5A induces silencing of its expression in TE13 cell line. Decreased mRNA and protein expression of RASSF5A was observed in ESCC tumor tissues and was associated with RASSF5A CpG island 1 methylation status. Unlike RASSF5A, expression variation of RASSF5B and RASSF5C was not found in ESCC tissues. Aberrant promoter methylation of RASSF5C was also not found in ESCC. RASSF5A methylation and protein expression were independently associated with ESCC patients’ survival. These data indicated that the inactivation of RASSF5A through CpG island 1 methylation may play an important role in ESCC carcinogenesis, RASSF5A may be a functional tumor suppressor and may serve as a prognostic biomarker for ESCC.
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Literature
1.
go back to reference Nagaraja V, Eslick GD (2014) Forthcoming prognostic markers for esophageal cancer: a systematic review and meta-analysis. J Gastrointest Oncol 5:67–76PubMedCentralPubMed Nagaraja V, Eslick GD (2014) Forthcoming prognostic markers for esophageal cancer: a systematic review and meta-analysis. J Gastrointest Oncol 5:67–76PubMedCentralPubMed
2.
go back to reference Shahbaz Sarwar CM, Luketich JD, Landreneau RJ, Abbas G (2010) Esophageal cancer: an update. Int J Surg 8:417–422PubMedCrossRef Shahbaz Sarwar CM, Luketich JD, Landreneau RJ, Abbas G (2010) Esophageal cancer: an update. Int J Surg 8:417–422PubMedCrossRef
3.
go back to reference Sun G, Wang S, Hu X, Su J, Huang T, Yu J, Tang L, Gao W, Wang JS (2007) Fumonisin B1 contamination of home-grown corn in high-risk areas for esophageal and liver cancer in China. Food Addit Contam 24:181–185PubMedCrossRef Sun G, Wang S, Hu X, Su J, Huang T, Yu J, Tang L, Gao W, Wang JS (2007) Fumonisin B1 contamination of home-grown corn in high-risk areas for esophageal and liver cancer in China. Food Addit Contam 24:181–185PubMedCrossRef
4.
go back to reference Guohong Z, Min S, Duenmei W, Songnian H, Min L, Jinsong L, Hongbin L, Feng Z, Dongping T, Heling Y, Zhicai L, Shiyong L, Quansheng G, Xiaoyun L, Yuxia G (2010) Genetic heterogeneity of oesophageal cancer in high-incidence areas of southern and northern China. PLoS ONE 5:e9668PubMedCentralPubMedCrossRef Guohong Z, Min S, Duenmei W, Songnian H, Min L, Jinsong L, Hongbin L, Feng Z, Dongping T, Heling Y, Zhicai L, Shiyong L, Quansheng G, Xiaoyun L, Yuxia G (2010) Genetic heterogeneity of oesophageal cancer in high-incidence areas of southern and northern China. PLoS ONE 5:e9668PubMedCentralPubMedCrossRef
5.
go back to reference Cully M, Downward J (2008) SnapShot: Ras Signaling. Cell 133 (1292–1292):e1PubMed Cully M, Downward J (2008) SnapShot: Ras Signaling. Cell 133 (1292–1292):e1PubMed
6.
go back to reference Richter AM, Pfeifer GP, Dammann RH (2009) The RASSF proteins in cancer; from epigenetic silencing to functional characterization. Biochim Biophys Acta 1796:114–128PubMed Richter AM, Pfeifer GP, Dammann RH (2009) The RASSF proteins in cancer; from epigenetic silencing to functional characterization. Biochim Biophys Acta 1796:114–128PubMed
7.
go back to reference Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP (2000) Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat Genet 25:315–319PubMedCrossRef Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP (2000) Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat Genet 25:315–319PubMedCrossRef
8.
9.
go back to reference Guo W, Dong Z, Chen Z, Yang Z, Wen D, Kuang G, Guo Y, Shan B (2009) Aberrant CpG Island hypermethylation of RASSF1A in gastric cardia adenocarcinoma. Cancer Invest 27:459–465PubMedCrossRef Guo W, Dong Z, Chen Z, Yang Z, Wen D, Kuang G, Guo Y, Shan B (2009) Aberrant CpG Island hypermethylation of RASSF1A in gastric cardia adenocarcinoma. Cancer Invest 27:459–465PubMedCrossRef
10.
go back to reference Guo W, Cui L, Wang C, Guo Y, Shen S, Kuang G, Dong Z (2014) Decreased expression of RASSF1A and up-regulation of RASSF1C is associated with esophageal squamous cell carcinoma. Clin Exp Metastasis 31:521–533PubMedCrossRef Guo W, Cui L, Wang C, Guo Y, Shen S, Kuang G, Dong Z (2014) Decreased expression of RASSF1A and up-regulation of RASSF1C is associated with esophageal squamous cell carcinoma. Clin Exp Metastasis 31:521–533PubMedCrossRef
11.
go back to reference Vavvas D, Li X, Avruch J, Zhang XF (1998) Identification of Nore1 as a potential Ras effector. J Biol Chem 273:5439–5442PubMedCrossRef Vavvas D, Li X, Avruch J, Zhang XF (1998) Identification of Nore1 as a potential Ras effector. J Biol Chem 273:5439–5442PubMedCrossRef
12.
go back to reference Tommasi S, Dammann R, Jin SG, Zhang XF, Avruch J, Pfeifer GP (2002) RASSF3 and NORE1: identification and cloning of two human homologues of the putative tumor suppressor gene RASSF1. Oncogene 21:2713–2720PubMedCrossRef Tommasi S, Dammann R, Jin SG, Zhang XF, Avruch J, Pfeifer GP (2002) RASSF3 and NORE1: identification and cloning of two human homologues of the putative tumor suppressor gene RASSF1. Oncogene 21:2713–2720PubMedCrossRef
13.
go back to reference Hesson L, Dallol A, Minna JD, Maher ER, Latif F (2003) NORE1A, a homologue of RASSF1A tumour suppressor gene is inactivated in human cancers. Oncogene 22:947–954PubMedCrossRef Hesson L, Dallol A, Minna JD, Maher ER, Latif F (2003) NORE1A, a homologue of RASSF1A tumour suppressor gene is inactivated in human cancers. Oncogene 22:947–954PubMedCrossRef
14.
go back to reference Shinmura K, Tao H, Nagura K, Goto M, Matsuura S, Mochizuki T, Suzuki K, Tanahashi M, Niwa H, Ogawa H, Sugimura H (2011) Suppression of hydroxyurea-induced centrosome amplification by NORE1A and down-regulation of NORE1A mRNA expression in non-small cell lung carcinoma. Lung Cancer 71:19–27PubMedCrossRef Shinmura K, Tao H, Nagura K, Goto M, Matsuura S, Mochizuki T, Suzuki K, Tanahashi M, Niwa H, Ogawa H, Sugimura H (2011) Suppression of hydroxyurea-induced centrosome amplification by NORE1A and down-regulation of NORE1A mRNA expression in non-small cell lung carcinoma. Lung Cancer 71:19–27PubMedCrossRef
15.
go back to reference Lee CK, Lee JH, Lee MG, Jeong SI, Ha TK, Kang MJ, Ryu BK, Hwangbo Y, Shim JJ, Jang JY, Lee KY, Kim HJ, Chi SG (2010) Epigenetic inactivation of the NORE1 gene correlates with malignant progression of colorectal tumors. BMC Cancer 10:577PubMedCentralPubMedCrossRef Lee CK, Lee JH, Lee MG, Jeong SI, Ha TK, Kang MJ, Ryu BK, Hwangbo Y, Shim JJ, Jang JY, Lee KY, Kim HJ, Chi SG (2010) Epigenetic inactivation of the NORE1 gene correlates with malignant progression of colorectal tumors. BMC Cancer 10:577PubMedCentralPubMedCrossRef
16.
go back to reference Calvisi DF, Donninger H, Vos MD, Birrer MJ, Gordon L, Leaner V, Clark GJ (2009) NORE1A tumor suppressor candidate modulates p21CIP1 via p53. Cancer Res 69:4629–4637PubMedCrossRef Calvisi DF, Donninger H, Vos MD, Birrer MJ, Gordon L, Leaner V, Clark GJ (2009) NORE1A tumor suppressor candidate modulates p21CIP1 via p53. Cancer Res 69:4629–4637PubMedCrossRef
17.
go back to reference Geli J, Kogner P, Lanner F, Natalishvili N, Juhlin C, Kiss N, Clark GJ, Ekström TJ, Farnebo F, Larsson C (2008) Assessment of NORE1A as a putative tumor suppressor in human neuroblastoma. Int J Cancer 123:389–394PubMedCrossRef Geli J, Kogner P, Lanner F, Natalishvili N, Juhlin C, Kiss N, Clark GJ, Ekström TJ, Farnebo F, Larsson C (2008) Assessment of NORE1A as a putative tumor suppressor in human neuroblastoma. Int J Cancer 123:389–394PubMedCrossRef
18.
go back to reference Djos A, Martinsson T, Kogner P, Carén H (2012) The RASSF gene family members RASSF5, RASSF6 and RASSF7 show frequent DNA methylation in neuroblastoma. Mol Cancer 11:40PubMedCentralPubMedCrossRef Djos A, Martinsson T, Kogner P, Carén H (2012) The RASSF gene family members RASSF5, RASSF6 and RASSF7 show frequent DNA methylation in neuroblastoma. Mol Cancer 11:40PubMedCentralPubMedCrossRef
19.
go back to reference Nakamura N, Carney JA, Jin L, Kajita S, Pallares J, Zhang H, Qian X, Sebo TJ, Erickson LA, Lloyd RV (2005) RASSF1A and NORE1A methylation and BRAFV600E mutations in thyroid tumors. Lab Invest 85:1065–1075PubMedCrossRef Nakamura N, Carney JA, Jin L, Kajita S, Pallares J, Zhang H, Qian X, Sebo TJ, Erickson LA, Lloyd RV (2005) RASSF1A and NORE1A methylation and BRAFV600E mutations in thyroid tumors. Lab Invest 85:1065–1075PubMedCrossRef
20.
go back to reference Irimia M, Fraga MF, Sanchez-Cespedes M, Esteller M (2004) CpG island promoter hypermethylation of the Ras-effector gene NORE1A occurs in the context of a wild-type K-ras in lung cancer. Oncogene 23:8695–8699PubMedCrossRef Irimia M, Fraga MF, Sanchez-Cespedes M, Esteller M (2004) CpG island promoter hypermethylation of the Ras-effector gene NORE1A occurs in the context of a wild-type K-ras in lung cancer. Oncogene 23:8695–8699PubMedCrossRef
21.
go back to reference Steinmann K, Sandner A, Schagdarsurengin U, Dammann RH (2009) Frequent promoter hypermethylation of tumor-related genes in head and neck squamous cell carcinoma. Oncol Rep 22:1519–1526PubMed Steinmann K, Sandner A, Schagdarsurengin U, Dammann RH (2009) Frequent promoter hypermethylation of tumor-related genes in head and neck squamous cell carcinoma. Oncol Rep 22:1519–1526PubMed
22.
go back to reference Geli J, Kiss N, Lanner F, Foukakis T, Natalishvili N, Larsson O, Kogner P, Höög A, Clark GJ, Ekström TJ, Bäckdahl M, Farnebo F, Larsson C (2007) The Ras effectors NORE1A and RASSF1A are frequently inactivated in pheochromocytoma and abdominal paraganglioma. Endocr Relat Cancer 14:125–134PubMedCrossRef Geli J, Kiss N, Lanner F, Foukakis T, Natalishvili N, Larsson O, Kogner P, Höög A, Clark GJ, Ekström TJ, Bäckdahl M, Farnebo F, Larsson C (2007) The Ras effectors NORE1A and RASSF1A are frequently inactivated in pheochromocytoma and abdominal paraganglioma. Endocr Relat Cancer 14:125–134PubMedCrossRef
23.
go back to reference Lorente A, Mueller W, Urdangarín E, Lázcoz P, Lass U, von Deimling A, Castresana JS (2009) RASSF1A, BLU, NORE1A, PTEN and MGMT expression and promoter methylation in gliomas and glioma cell lines and evidence of deregulated expression of de novo DNMTs. Brain Pathol 19:279–292PubMedCrossRef Lorente A, Mueller W, Urdangarín E, Lázcoz P, Lass U, von Deimling A, Castresana JS (2009) RASSF1A, BLU, NORE1A, PTEN and MGMT expression and promoter methylation in gliomas and glioma cell lines and evidence of deregulated expression of de novo DNMTs. Brain Pathol 19:279–292PubMedCrossRef
24.
go back to reference Macheiner D, Heller G, Kappel S, Bichler C, Stättner S, Ziegler B, Kandioler D, Wrba F, Schulte-Hermann R, Zöchbauer-Müller S, Grasl-Kraupp B (2006) NORE1B, a candidate tumor suppressor, is epigenetically silenced in human hepatocellular carcinoma. J Hepatol 45:81–89PubMedCrossRef Macheiner D, Heller G, Kappel S, Bichler C, Stättner S, Ziegler B, Kandioler D, Wrba F, Schulte-Hermann R, Zöchbauer-Müller S, Grasl-Kraupp B (2006) NORE1B, a candidate tumor suppressor, is epigenetically silenced in human hepatocellular carcinoma. J Hepatol 45:81–89PubMedCrossRef
25.
go back to reference Macheiner D, Gauglhofer C, Rodgarkia-Dara C, Grusch M, Brachner A, Bichler C, Kandioler D, Sutterlüty H, Mikulits W, Schulte-Hermann R, Grasl-Kraupp B (2009) NORE1B is a putative tumor suppressor in hepatocarcinogenesis and may act via RASSF1A. Cancer Res 69:235–242PubMedCrossRef Macheiner D, Gauglhofer C, Rodgarkia-Dara C, Grusch M, Brachner A, Bichler C, Kandioler D, Sutterlüty H, Mikulits W, Schulte-Hermann R, Grasl-Kraupp B (2009) NORE1B is a putative tumor suppressor in hepatocarcinogenesis and may act via RASSF1A. Cancer Res 69:235–242PubMedCrossRef
26.
go back to reference Kondo Y, Shen L, Issa JP (2003) Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer. Mol Cell Biol 23:206–215PubMedCentralPubMedCrossRef Kondo Y, Shen L, Issa JP (2003) Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer. Mol Cell Biol 23:206–215PubMedCentralPubMedCrossRef
27.
go back to reference Meng CF, Zhu XJ, Peng G, Dai DQ (2007) Re-expression of methylation-induced tumor suppressor gene silencing is associated with the state of histone modification in gastric cancer cell lines. World J Gastroenterol 13:6166–6171PubMedCentralPubMedCrossRef Meng CF, Zhu XJ, Peng G, Dai DQ (2007) Re-expression of methylation-induced tumor suppressor gene silencing is associated with the state of histone modification in gastric cancer cell lines. World J Gastroenterol 13:6166–6171PubMedCentralPubMedCrossRef
28.
go back to reference Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408PubMedCrossRef Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408PubMedCrossRef
29.
go back to reference Das PM, Ramachandran K, vanWert J, Singal R (2004) Chromatin immunoprecipitation assay. Biotechniques 37:961–969PubMed Das PM, Ramachandran K, vanWert J, Singal R (2004) Chromatin immunoprecipitation assay. Biotechniques 37:961–969PubMed
30.
go back to reference Yu L, Liu C, Vandeusen J, Becknell B, Dai Z, Wu YZ, Raval A, Liu TH, Ding W, Mao C, Liu S, Smith LT, Lee S, Rassenti L, Marcucci G, Byrd J, Caligiuri MA, Plass C (2005) Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia. Nat Genet 37:265–274PubMedCrossRef Yu L, Liu C, Vandeusen J, Becknell B, Dai Z, Wu YZ, Raval A, Liu TH, Ding W, Mao C, Liu S, Smith LT, Lee S, Rassenti L, Marcucci G, Byrd J, Caligiuri MA, Plass C (2005) Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia. Nat Genet 37:265–274PubMedCrossRef
31.
go back to reference Sasaki M, Anast J, Bassett W, Kawakami T, Sakuragi N, Dahiya R (2003) Bisulfite conversion-specific and methylation-specific PCR: a sensitive technique for accurate evaluation of CpG methylation. Biochem Biophys Res Commun 309:305–309PubMedCrossRef Sasaki M, Anast J, Bassett W, Kawakami T, Sakuragi N, Dahiya R (2003) Bisulfite conversion-specific and methylation-specific PCR: a sensitive technique for accurate evaluation of CpG methylation. Biochem Biophys Res Commun 309:305–309PubMedCrossRef
32.
go back to reference Umemoto M, Yokoyama Y, Sato S, Tsuchida S, Al-Mulla F, Saito Y (2001) Carbonyl reductase as a significant predictor of survival and lymph node metastasis in epithelial ovarian cancer. Br J Cancer 85:1032–1036PubMedCentralPubMedCrossRef Umemoto M, Yokoyama Y, Sato S, Tsuchida S, Al-Mulla F, Saito Y (2001) Carbonyl reductase as a significant predictor of survival and lymph node metastasis in epithelial ovarian cancer. Br J Cancer 85:1032–1036PubMedCentralPubMedCrossRef
33.
go back to reference Li LC, Dahiya R (2002) MethPrimer: designing primers for methylation PCRs. Bioinformatics 18:1427–1431PubMedCrossRef Li LC, Dahiya R (2002) MethPrimer: designing primers for methylation PCRs. Bioinformatics 18:1427–1431PubMedCrossRef
35.
go back to reference Di Gioia S, Bianchi P, Destro A, Grizzi F, Malesci A, Laghi L, Levrero M, Morabito A, Roncalli M (2006) Quantitative evaluation of RASSF1A methylation in the non-lesional, regenerative and neoplastic liver. BMC Cancer 6:89PubMedCentralPubMedCrossRef Di Gioia S, Bianchi P, Destro A, Grizzi F, Malesci A, Laghi L, Levrero M, Morabito A, Roncalli M (2006) Quantitative evaluation of RASSF1A methylation in the non-lesional, regenerative and neoplastic liver. BMC Cancer 6:89PubMedCentralPubMedCrossRef
36.
go back to reference Hesson L, Bièche I, Krex D, Criniere E, Hoang-Xuan K, Maher ER, Latif F (2004) Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas. Oncogene 23:2408–2419PubMedCrossRef Hesson L, Bièche I, Krex D, Criniere E, Hoang-Xuan K, Maher ER, Latif F (2004) Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas. Oncogene 23:2408–2419PubMedCrossRef
37.
go back to reference Chow LS, Lo KW, Kwong J, Wong AY, Huang DP (2004) Aberrant methylation of RASSF4/AD037 in nasopharyngeal carcinoma. Oncol Rep 12:781–787PubMed Chow LS, Lo KW, Kwong J, Wong AY, Huang DP (2004) Aberrant methylation of RASSF4/AD037 in nasopharyngeal carcinoma. Oncol Rep 12:781–787PubMed
38.
go back to reference Lázcoz P, Muñoz J, Nistal M, Pestaña A, Encío I, Castresana JS (2006) Frequent promoter hypermethylation of RASSF1A and CASP8 in neuroblastoma. BMC Cancer 6:254PubMedCentralPubMedCrossRef Lázcoz P, Muñoz J, Nistal M, Pestaña A, Encío I, Castresana JS (2006) Frequent promoter hypermethylation of RASSF1A and CASP8 in neuroblastoma. BMC Cancer 6:254PubMedCentralPubMedCrossRef
39.
go back to reference Chen SH, Chan SC, Chao YK, Yen TC (2013) Detection of synchronous cancers by fluorodeoxyglucose positron emission tomography/computed tomography during primary staging workup for esophageal squamous cell carcinoma in Taiwan. PLoS ONE 8:e82812PubMedCentralPubMedCrossRef Chen SH, Chan SC, Chao YK, Yen TC (2013) Detection of synchronous cancers by fluorodeoxyglucose positron emission tomography/computed tomography during primary staging workup for esophageal squamous cell carcinoma in Taiwan. PLoS ONE 8:e82812PubMedCentralPubMedCrossRef
40.
go back to reference Brock MV, Hooker CM, Ota-Machida E, Han Y, Guo M, Ames S, Glöckner S, Piantadosi S, Gabrielson E, Pridham G, Pelosky K, Belinsky SA, Yang SC, Baylin SB, Herman JG (2008) DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med 358:1118–1128PubMedCrossRef Brock MV, Hooker CM, Ota-Machida E, Han Y, Guo M, Ames S, Glöckner S, Piantadosi S, Gabrielson E, Pridham G, Pelosky K, Belinsky SA, Yang SC, Baylin SB, Herman JG (2008) DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med 358:1118–1128PubMedCrossRef
Metadata
Title
RASSF5A, a candidate tumor suppressor, is epigenetically inactivated in esophageal squamous cell carcinoma
Authors
Wei Guo
Cong Wang
Yanli Guo
Supeng Shen
Xin Guo
Gang Kuang
Zhiming Dong
Publication date
01-01-2015
Publisher
Springer Netherlands
Published in
Clinical & Experimental Metastasis / Issue 1/2015
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-015-9693-6

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