Silencing of RASSF3 by DNA Hypermethylation Is Associated with Tumorigenesis in Somatotroph Adenomas

被引:22
作者
Peng, Hu [1 ]
Liu, Huanhai [1 ]
Zhao, Shuwei [1 ]
Wu, Jian [1 ]
Fan, Jingping [1 ]
Liao, Jianchun [1 ]
机构
[1] Second Mil Med Univ, Changzheng Hosp, Dept Otolaryngol Head & Neck Surg, Shanghai, Peoples R China
关键词
TUMOR-SUPPRESSOR GENE; PITUITARY-ADENOMAS; METHYLATION LEVELS; PROMOTER; PATHOGENESIS; CANCER; IDENTIFICATION; INACTIVATION; DISEASE;
D O I
10.1371/journal.pone.0059024
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The pathogenic mechanisms underlying pituitary somatotroph adenoma formation, progression are poorly understood. To identify candidate tumor suppressor genes involved in pituitary somatotroph adenoma tumorigenesis, we used HG18 CpG plus Promoter Microarray in 27 human somatotroph adenomas and 4 normal human adenohypophyses. RASSF3 was found with frequent methylation of CpG island in its promoter region in somatotroph adenomas but rarely in adenohypophyses. This result was confirmed by pyrosequencing analysis. We also found that RASSF3 mRNA level correlated negatively to its gene promoter methylation level. RASSF3 hypermethylation and downregulation was also observed in rat GH3 and mouse GT1.1 somatotroph adenoma cell lines. 5-Aza-2' deoxycytidine and trichostatin-A treatment induced RASSF3 promoter demethylation, and restored its expression in GH3 and GT1.1 cell lines. RASSF3 overexpression in GH3 and GT1.1 cells inhibited proliferation, induced apoptosis accompanied by increased Bax, p53, and caspase-3 protein and decreased Bcl-2 protein expression. We also found that the antitumor effect of RASSF3 was p53 dependent, and p53 knockdown blocked RASSF3-induced apoptosis and growth inhibition. Taken together, our results suggest that hypermethylation-induced RASSF3 silencing plays an important role in the tumorigenesis of pituitary somatotroph adenomas.
引用
收藏
页数:10
相关论文
共 32 条
[1]   The cytogenesis and pathogenesis of pituitary adenomas [J].
Asa, SL ;
Ezzat, S .
ENDOCRINE REVIEWS, 1998, 19 (06) :798-827
[2]   The pathogenesis of pituitary tumours [J].
Asa, SL ;
Ezzat, S .
NATURE REVIEWS CANCER, 2002, 2 (11) :836-849
[3]   The Pathogenesis of Pituitary Tumors [J].
Asa, Sylvia L. ;
Ezzat, Shereen .
ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE, 2009, 4 :97-126
[4]   NORE1A Tumor Suppressor Candidate Modulates p21CIP1 via p53 [J].
Calvisi, Diego F. ;
Donninger, Howard ;
Vos, Michele D. ;
Birrer, Michael J. ;
Gordon, Laura ;
Leaner, Virna ;
Clark, Geoffrey J. .
CANCER RESEARCH, 2009, 69 (11) :4629-4637
[5]   Lineage-Specific Restraint of Pituitary Gonadotroph Cell Adenoma Growth [J].
Chesnokova, Vera ;
Zonis, Svetlana ;
Zhou, Cuiqi ;
Ben-Shlomo, Anat ;
Wawrowsky, Kolja ;
Toledano, Yoel ;
Tong, Yunguang ;
Kovacs, Kalman ;
Scheithauer, Bernd ;
Melmed, Shlomo .
PLOS ONE, 2011, 6 (03)
[6]   The RASSF gene family members RASSF5, RASSF6 and RASSF7 show frequent DNA methylation in neuroblastoma [J].
Djos, Anna ;
Martinsson, Tommy ;
Kogner, Per ;
Caren, Helena .
MOLECULAR CANCER, 2012, 11
[7]  
Dworakowska Dorota, 2011, Front Biosci (Schol Ed), V3, P105, DOI 10.2741/s136
[8]   Genesis of pituitary adenomas: state of the art [J].
Faglia, G ;
Spada, A .
JOURNAL OF NEURO-ONCOLOGY, 2001, 54 (02) :95-110
[9]   Mechanisms of disease: Gene silencing in cancer in association with promoter hypermethylation [J].
Herman, JG ;
Baylin, SB .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 349 (21) :2042-2054
[10]   Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas [J].
Hesson, L ;
Bièche, I ;
Krex, D ;
Criniere, E ;
Hoang-Xuan, K ;
Maher, ER ;
Latif, F .
ONCOGENE, 2004, 23 (13) :2408-2419