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Frequent hypermethylation of CpG islands and loss of expression of the 14-3-3 σ gene in human hepatocellular carcinoma

Abstract

The 14-3-3 σ gene has been implicated in G2/M cell cycle arrest by p53. Frequent inactivation of the 14-3-3 σ gene by hypermethylation of CpG islands has recently been reported in human breast carcinoma. The aim of this study was to examine the methylation status of CpG islands of the 14-3-3 σ gene in hepatocellular carcinoma (HCC). The methylation status of the 14-3-3 σ gene was evaluated in four normal liver tissues and 19 paired specimens of carcinoma and adjacent non-tumorous liver tissues using bisulfite-single strand conformation polymorphism (bisulfite-SSCP), a combination of sodium bisulfite modification and fluorescence-based polymerase chain reaction (PCR)-SSCP. The 14-3-3 σ protein expression was examined by immunohistochemical staining. Hypermethylation of CpG islands of the 14-3-3 σ gene was detected in 89% (17/19) of the HCC tissues but not in any of the four normal liver tissues. All of the 14 methylation-positive HCC samples analysed by immunohistochemistry showed loss of 14-3-3 σ expression, while both of the methylation-negative HCC samples retained the expression, and a significant correlation was found between methylation and loss of expression. Lower levels of methylation were detected in adjacent non-tumorous liver tissues (6/16 in cirrhotic tissues and 1/3 in chronic hepatitis tissues), but the 14-3-3 σ expression was retained in all of these tissues. In a methylation-positive HCC cell line, HLE, 5-aza-2′-deoxycytidine (5-aza-dC)-induced demethylation of CpG islands led to reactivation of gene expression, indicating that hypermethylation plays a causal role in inactivation of the 14-3-3 σ gene in HCC. Hypermethylation and the resulting loss of expression of the 14-3-3 σ gene corresponds to one of the most common abnormalities reported to date in HCC, suggesting their crucial role in the development and/or progression of HCC.

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References

  • Ahuja N, Li Q, Mohan AL, Baylin SB and Issa JP. . 1998 Cancer Res. 58: 5489–5494.

  • Baylin SB, Herman JG, Graff JR, Vertino PM and Issa JP. . 1998 Adv. Cancer Res. 72: 141–196.

  • Belinsky SA, Nikula KJ, Palmisano WA, Michels R, Saccomanno G, Gabrielson E, Baylin SB and Herman JG. . 1998 Proc. Natl. Acad. Sci. USA 95: 11891–11896.

  • Burri N and Chaubert P. . 1999 Biotechniques 26: 232–234.

  • Chan TA, Hermeking H, Lengauer C, Kinzler KW and Vogelstein B. . 1999 Nature 401: 616–620.

  • Chaubert P, Gayer R, Zimmermann A, Fontolliet C, Stamm B, Bosman F and Shaw P. . 1997 Hepatology 25: 1376–1381.

  • Dellambra E, Patrone M, Sparatore B, Negri A, Ceciliani F, Bondanza S, Molina F, Cancedda FD and De Luca M. . 1995 J. Cell Sci. 108: 3569–3579.

  • el-Deiry WS. . 1998 Semin. Cancer Biol. 8: 345–357.

  • Ferguson AT, Evron E, Umbricht CB, Pandita TK, Chan TA, Hermeking H, Marks JR, Lambers AR, Futreal PA, Stampfer MR and Sukumar S. . 2000 Proc. Natl. Acad. Sci. USA 97: 6049–6054.

  • Gonzalgo ML, Hayashiba T, Bender CM, Pao MM, Tsai YC, Gonzales FA, Nguyen HD, Nguyen TT and Jones PA. . 1998 Cancer Res. 58: 1245–1252.

  • Herman JG, Graff JR, Myohanen S, Nelkin BD and Baylin SB. . 1996 Proc. Natl. Acad. Sci. USA 93: 9821–9826.

  • Herman JG. . 1999 Gastroenterology 116: 483–485.

  • Hermeking H, Lengauer C, Polyak K, He TC, Zhang L, Thiagalingam S, Kinzler KW and Vogelstein B. . 1997 Mol. Cell 1: 3–11.

  • Hsieh CL. . 1994 Mol. Cell. Biol. 14: 5487–5494.

  • Hsieh CJ, Klump B, Holzmann K, Borchard F, Gregor M and Porschen R. . 1998 Cancer Res. 58: 3942–3945.

  • Jones PA and Laird PW. . 1999 Nat. Genet. 11: 136–140.

  • Kamb A. . 1995 Trends Genet. 11: 136–140.

  • Klump B, Heieh C, Holzmann K, Gregor M and Porschen R. . 1998 Gastroenterology 115: 1381–1386.

  • Laronga C, Yang HY, Neal C and Lee MH. . 2000 J. Biol. Chem. 275: 23106–23112.

  • Kanai Y, Ushijima S, Tsuda H, Sakamoto M and Hirohashi S. . 2000 Cancer Lett. 148: 73–80.

  • Liew CT, Li HM, Lo KW, Leow CK, Chan JY, Lau WY, Lai PB, Chan JY, Wang XQ, Wu S and Lee JC. . 1999 Oncogene 18: 789–795.

  • Maekawa M, Sugano K, Kashiwabara H, Ushiama M, Fujita S, Yoshimori M and Kakizoe T. . 1999 Biochem. Biophys. Res. Commun. 262: 671–676.

  • Matsuda Y, Ichida T, Matsuzawa J, Sugimura K and Asakura H. . 1999 Gastroenterology 116: 394–400.

  • Melis R and White R. . 1999 Electrophoresis 20: 1055–1064.

  • Nagai H, Pineau P, Tiollais P, Buendia MA and Dejean A. . 1997 Oncogene 14: 2927–2933.

  • Nishida N, Fukuda Y, Ishizaki K and Nakao K. . 1997 Histol. Histopathol. 12: 1019–1025.

  • Okuda K. . 1992 Hepatology 15: 948–963.

  • Ostergaard M, Rasmussen HH, Nielsen HV, Vorum H, Orntoft TF, Wolf H and Celis JE. . 1997 Cancer Res. 57: 4111–4117.

  • Ozturk M. . 1999 Semin. Liver Dis. 19: 235–242.

  • Piwnica-Worms H. . 1999 Nature 401: 535–536.

  • Prasad GL, Valverius EM, McDuffie E and Cooper HL. . 1992 Cell Growth Differ. 3: 507–513.

  • Suzuki H, Itoh F, Toyota M, Kikuchi T, Kakiuchi H, Hinoda Y and Imai K. . 2000 Electrophoresis 21: 904–908.

  • Tajima M, Komuro M and Okinaga K. . 1998 Jpn. J. Cancer Res. 89: 262–268.

  • Vellucci VF, Germino FJ and Reiss M. . 1995 Gene 166: 213–220.

  • Wilentz RE, Geradts J, Maynard R, Offerhaus GJ, Kang M, Goggins M, Yeo CJ, Kern SE and Hruban RH. . 1998 Cancer Res. 58: 4740–4744.

  • Wong IHN, Lo YMD, Zhang J, Liew C-T, Ng MHL, Wong N, Lai PBS, Lau WY, Hjelm NM and Johnson PJ. . 1999 Cancer Res. 59: 71–73.

  • Yamamoto H, Adachi Y, Itoh F, Iku S, Matsuno K, Kusano M, Arimura Y, Endo T, Hinoda Y, Hosokawa M and Imai K. . 1999 Cancer Res. 59: 3313–3316.

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Acknowledgements

This work is supported by grants-in-aid from the Japanese Ministry of Education, Science, Sports and Culture and from the Ministry of Health and Welfare.

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Iwata, N., Yamamoto, H., Sasaki, S. et al. Frequent hypermethylation of CpG islands and loss of expression of the 14-3-3 σ gene in human hepatocellular carcinoma. Oncogene 19, 5298–5302 (2000). https://doi.org/10.1038/sj.onc.1203898

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