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Horm Metab Res 2014; 46(09): 644-650
DOI: 10.1055/s-0034-1383566
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Expression Analysis of GADD45γ, MEG3, and p8 in Pituitary Adenomas

I. Binse
1   Department of Nuclear Medicine, University Hospital Essen, Essen, Germany
,
B. Ueberberg
2   General Paediatrics, University Hospital Düsseldorf, Düsseldorf, Germany
,
I. E. Sandalcioglu
3   Nordstadt, Neurosurgery, Hospital Region Hannover, Hannover, Germany
,
J. Flitsch
4   Neurosurgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany
,
D. K. Luedecke
4   Neurosurgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany
,
K. Mann
5   Division of Endocrinology, Medical Center, University Hospital Essen, Essen, Germany
,
S. Petersenn
6   ENDOC, Center for Endocrine Tumors, Hamburg, Germany
› Author Affiliations
Further Information

Publication History

received 02 July 2013

accepted 04 June 2014

Publication Date:
15 August 2014 (online)

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Abstract

Preceding studies have indicated that aberrant expression levels rather than genetic changes of GADD45γ, MEG3, and p8 gene might play a role in the pathogenesis of pituitary adenomas. We analysed their expression in various normal human tissues and in different pituitary tumour types, and investigated GADD45γ mutations in a subset of adenomas. Absolute quantification by real-time RT-PCR was performed in 24 normal tissues as well as in 34 nonfunctioning, 24 somatotroph, 12 corticotroph adenomas, 4 prolactinomas, 1 FSHoma, and in 6 normal pituitaries. Furthermore, we investigated the relationship between clinical data and gene expression. A subset was screened for GADD45γ mutations by single strand conformation polymorphism analysis (SSCP) and sequencing. All normal human tissues expressed GADD45γ, MEG3, and p8 mRNA. For GADD45γ, significantly lower expression levels were found in nonfunctioning adenomas compared with normal pituitary and somatotroph adenomas. P8 and MEG3 mRNA levels were significantly lower in nonfunctioning and corticotroph adenomas compared with normal pituitary. Expression of GADD45γ was significantly higher in pituitary adenomas of female patients. No mutation was found in the GADD45γ gene. GADD45γ, MEG3, and p8 appear to have physiological functions in a variety of human tissues. GADD45γ, MEG3, and P8 may be involved in the pathogenesis of nonfunctioning and corticotroph pituitary tumours. Female gender seems to predispose to slightly higher GADD45γ expression in pituitary adenomas. Mutations of the GADD45γ are unlikely to be involved in the pathogenesis of pituitary adenomas.

Key words

growth arrest and DNA damage-inducible gene 45γ - maternally expressed gene 3 - protein 8 - mutation - polymorphism - pituitary tumour

Supporting Information

 

  • References

  • 1 Grossman AB, Korbonits M. Akting and cycling: a tale of the pituitary. Horm Res 2004; 62 (Suppl. 03) 117-123
    CrossrefPubMedSearch in Google Scholar
  • 2 Heaney AP, Melmed S. New pituitary oncogenes. Endocr Relat Cancer 2000; 7: 3-15
    CrossrefPubMedSearch in Google Scholar
  • 3 Cretu A, Sha X, Tront J, Hoffman B, Liebermann DA. Stress sensor Gadd45 genes as therapeutic targets in cancer. Cancer Ther 2009; 7: 268-276
    PubMedSearch in Google Scholar
  • 4 Sun L, Gong R, Wan B, Huang X, Wu C, Zhang X, Zhao S, Yu L. GADD45gamma, down-regulated in 65% hepatocellular carcinoma (HCC) from 23 chinese patients, inhibits cell growth and induces cell cycle G2/M arrest for hepatoma Hep-G2 cell lines. Mol Biol Rep 2003; 30: 249-253
    CrossrefPubMedSearch in Google Scholar
  • 5 Ying J, Srivastava G, Hsieh WS, Gao Z, Murray P, Liao SK, Ambinder R, Tao Q. The stress-responsive gene GADD45G is a functional tumor suppressor, with its response to environmental stresses frequently disrupted epigenetically in multiple tumors. Clin Cancer Res 2005; 11: 6442-6449
    CrossrefPubMedSearch in Google Scholar
  • 6 Zhang X, Sun H, Danila DC, Johnson SR, Zhou Y, Swearingen B, Klibanski A. Loss of expression of GADD45 gamma, a growth inhibitory gene, in human pituitary adenomas: implications for tumorigenesis. J Clin Endocrinol Metab 2002; 87: 1262-1267
    CrossrefPubMedSearch in Google Scholar
  • 7 Chung HK, Yi YW, Jung NC, Kim D, Suh JM, Kim H, Park KC, Kim DW, Hwang ES, Song JH, Ku BJ, Han HJ, Ro HK, Kim JM, Shong M. Gadd45gamma expression is reduced in anaplastic thyroid cancer and its reexpression results in apoptosis. J Clin Endocrinol Metab 2003; 88: 3913-3920
    CrossrefPubMedSearch in Google Scholar
  • 8 Bahar A, Bicknell JE, Simpson DJ, Clayton RN, Farrell WE. Loss of expression of the growth inhibitory gene GADD45gamma, in human pituitary adenomas, is associated with CpG island methylation. Oncogene 2004; 23: 936-944
    CrossrefPubMedSearch in Google Scholar
  • 9 Zhang X, Zhou Y, Mehta KR, Danila DC, Scolavino S, Johnson SR, Klibanski A. A pituitary-derived MEG3 isoform functions as a growth suppressor in tumor cells. J Clin Endocrinol Metab 2003; 88: 5119-5126
    CrossrefPubMedSearch in Google Scholar
  • 10 Zhao J, Dahle D, Zhou Y, Zhang X, Klibanski A. Hypermethylation of the promoter region is associated with the loss of MEG3 gene expression in human pituitary tumors. J Clin Endocrinol Metab 2005; 90: 2179-2186
    CrossrefPubMedSearch in Google Scholar
  • 11 Gejman R, Batista DL, Zhong Y, Zhou Y, Zhang X, Swearingen B, Stratakis CA, Hedley-Whyte ET, Klibanski A. Selective loss of MEG3 expression and intergenic differentially methylated region hypermethylation in the MEG3/DLK1 locus in human clinically nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 2008; 93: 4119-4125
    CrossrefPubMedSearch in Google Scholar
  • 12 Vasseur S, Vidal Mallo G, Fiedler F, Bodeker H, Canepa E, Moreno S, Iovanna JL. Cloning and expression of the human p8, a nuclear protein with mitogenic activity. Eur J Biochem 1999; 259: 670-675
    CrossrefPubMedSearch in Google Scholar
  • 13 Chowdhury UR, Samant RS, Fodstad O, Shevde LA. Emerging role of nuclear protein 1 (NUPR1) in cancer biology. Cancer Metastasis Rev 2009; 28: 225-232
    CrossrefPubMedSearch in Google Scholar
  • 14 Iovanna JL. Expression of the stress-associated protein p8 is a requisite for tumor development. Int J Gastrointest Cancer 2002; 31: 89-98
    CrossrefPubMedSearch in Google Scholar
  • 15 Ito Y, Yoshida H, Motoo Y, Miyoshi E, Iovanna JL, Tomoda C, Uruno T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F, Matsuura N, Kuma K, Miyauchi A. Expression and cellular localization of p8 protein in thyroid neoplasms. Cancer Lett 2003; 201: 237-244
    CrossrefPubMedSearch in Google Scholar
  • 16 Mohammad HP, Seachrist DD, Quirk CC, Nilson JH. Reexpression of p8 contributes to tumorigenic properties of pituitary cells and appears in a subset of prolactinomas in transgenic mice that hypersecrete luteinizing hormone. Mol Endocrinol 2004; 18: 2583-2593
    CrossrefPubMedSearch in Google Scholar
  • 17 Ree AH, Pacheco MM, Tvermyr M, Fodstad O, Brentani MM. Expression of a novel factor, com1, in early tumor progression of breast cancer. Clin Cancer Res 2000; 6: 1778-1783
    PubMedSearch in Google Scholar
  • 18 Niveiro M, Aranda FI, Peiro G, Alenda C, Pico A. Immunohistochemical analysis of tumor angiogenic factors in human pituitary adenomas. Hum Pathol 2005; 36: 1090-1095
    CrossrefPubMedSearch in Google Scholar
  • 19 Zhou Y, Zhong Y, Wang Y, Zhang X, Batista DL, Gejman R, Ansell PJ, Zhao J, Weng C, Klibanski A. Activation of p53 by MEG3 non-coding RNA. J Biol Chem 2007; 282: 24731-24742
    CrossrefPubMedSearch in Google Scholar
  • 20 Gordon FE, Nutt CL, Cheunsuchon P, Nakayama Y, Provencher KA, Rice KA, Zhou Y, Zhang X, Klibanski A. Increased expression of angiogenic genes in the brains of mouse meg3-null embryos. Endocrinology 151: 2443-2452
    PubMed
  • 21 Cheunsuchon P, Zhou Y, Zhang X, Lee H, Chen W, Nakayama Y, Rice KA, Tessa Hedley-Whyte E, Swearingen B, Klibanski A. Silencing of the imprinted DLK1-MEG3 locus in human clinically nonfunctioning pituitary adenomas. Am J Pathol 179: 2120-2130
    PubMed
  • 22 Miyoshi N, Wagatsuma H, Wakana S, Shiroishi T, Nomura M, Aisaka K, Kohda T, Surani MA, Kaneko-Ishino T, Ishino F. Identification of an imprinted gene, Meg3/Gtl2 and its human homologue MEG3, first mapped on mouse distal chromosome 12 and human chromosome 14q. Genes Cells 2000; 5: 211-220
    CrossrefPubMedSearch in Google Scholar
  • 23 Jiang WG, Davies G, Martin TA, Kynaston H, Mason MD, Fodstad O. Com-1/p8 acts as a putative tumour suppressor in prostate cancer. Int J Mol Med 2006; 18: 981-986
    PubMedSearch in Google Scholar