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Horm Metab Res 2015; 47(09): 656-661
DOI: 10.1055/s-0034-1398560
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

DAX1 Overexpression in Pediatric Adrenocortical Tumors: A Synergic Role with SF1 in Tumorigenesis

G. R. V. de Sousa
1   Unidade de Suprarrenal & Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular (Laboratório de Investigação Medica, LIM 42) da Disciplina de Endocrinologia do Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
,
I. C. Soares
2   Hospital do Câncer de Barretos, RO, Brazil
,
A. M. Faria
1   Unidade de Suprarrenal & Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular (Laboratório de Investigação Medica, LIM 42) da Disciplina de Endocrinologia do Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
,
V. B. Domingues
3   Divisão de Anatomia Patologia, Laboratório de Patologia Hepática/LIM14 do Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, SP, Brazil
,
A. Wakamatsu
3   Divisão de Anatomia Patologia, Laboratório de Patologia Hepática/LIM14 do Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, SP, Brazil
,
A. M. Lerario
1   Unidade de Suprarrenal & Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular (Laboratório de Investigação Medica, LIM 42) da Disciplina de Endocrinologia do Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
4   Serviço de Endocrinologia, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
,
V. A. F. Alves
3   Divisão de Anatomia Patologia, Laboratório de Patologia Hepática/LIM14 do Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, SP, Brazil
,
M. C. N. Zerbini
3   Divisão de Anatomia Patologia, Laboratório de Patologia Hepática/LIM14 do Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, SP, Brazil
,
B. B. Mendonca
1   Unidade de Suprarrenal & Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular (Laboratório de Investigação Medica, LIM 42) da Disciplina de Endocrinologia do Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
,
M. C. B. V. Fragoso
1   Unidade de Suprarrenal & Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular (Laboratório de Investigação Medica, LIM 42) da Disciplina de Endocrinologia do Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
4   Serviço de Endocrinologia, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
,
A. C. Latronico
1   Unidade de Suprarrenal & Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular (Laboratório de Investigação Medica, LIM 42) da Disciplina de Endocrinologia do Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
,
M. Q. Almeida
1   Unidade de Suprarrenal & Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular (Laboratório de Investigação Medica, LIM 42) da Disciplina de Endocrinologia do Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
4   Serviço de Endocrinologia, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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Publikationsverlauf

received 23. September 2014

accepted 18. Dezember 2014

Publikationsdatum:
18. Mai 2015 (online)

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Abstract

DAX1 transcription factor is a key determinant of adrenogonadal development, acting as a repressor of SF1 targets in steroidogenesis. It was recently demonstrated that DAX1 regulates pluripotency and differentiation in murine embryonic stem cells. In this study, we investigated DAX1 expression in adrenocortical tumors (ACTs) and correlated it with SF1 expression and clinical parameters. DAX1 and SF1 protein expression were assessed in 104 ACTs from 34 children (25 clinically benign and 9 malignant) and 70 adults (40 adenomas and 30 carcinomas). DAX1 gene expression was studied in 49 ACTs by quantitative real-time PCR. A strong DAX1 protein expression was demonstrated in 74% (25 out of 34) and 24% (17 out of 70) of pediatric and adult ACTs, respectively (χ2=10.1, p=0.002). In the pediatric group, ACTs with a strong DAX1 expression were diagnosed at earlier ages than ACTs with weak expression [median 1.2 (range, 0.5–4.5) vs. 2.2 (0.9–9.4), p=0.038]. DAX1 expression was not associated with functional status in ACTs. Interestingly, a positive correlation was observed between DAX1 and SF1 protein expression in both pediatric and adult ACTs (r=0.55 for each group separately; p<0.0001). In addition, DAX1 gene expression was significantly correlated with SF1 gene expression (p<0.0001, r=0.54). In conclusion, DAX1 strong protein expression was more frequent in pediatric than in adult ACTs. Additionally, DAX1 and SF1 expression positively correlated in ACTs, suggesting that these transcription factors might cooperate in adrenocortical tumorigenesis.

Key words

DAX1 - SF1 - expression - adrenocortical tumors
 

  • References

  • 1 Muscatelli F, Strom TM, Walker AP, Zanaria E, Recan D, Meindl A, Bardoni B, Guioli S, Zehetner G, Rabl W, Schwarz HP, Kaplan J-C, Camerino G, Meitinger T, Monaco AP. Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature 1994; 372: 672-676
    CrossrefPubMedGoogle Scholar
  • 2 Zanaria E, Muscatelli F, Bardoni B, Strom TM, Guioli S, Guo W, Lalli E, Moser C, Walker AP, McCabe ER, Meitingr T, Monaco AP, Sassone-Corsi P, Camerino G. An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 1994; 372: 635-641
    CrossrefPubMedGoogle Scholar
  • 3 Achermann JC, Ito M, Hindmarsh PC, Jameson JL. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet 1999; 22: 125-126
    CrossrefPubMedGoogle Scholar
  • 4 Lalli E, Melner MH, Stocco DM, Sassone-Corsi P. DAX-1 blocks steroid production at multiple levels. Endocrinology 1998; 139: 4237-4243
    CrossrefPubMedGoogle Scholar
  • 5 Latronico AC, Chrousos GP. Extensive personal experience: adrenocortical tumors. J Clin Endocrinol Metab 1997; 82: 1317-1324
    CrossrefPubMedGoogle Scholar
  • 6 Almeida MQ, Latronico AC. The molecular pathogenesis of childhood adrenocortical tumors. Horm Metab Res 2007; 39: 461-466
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 7 Sbiera S, Schmull S, Assie G, Voelker HU, Kraus L, Beyer M, Ragazzon B, Beuschlein F, Willenberg HS, Hahner S, Saeger W, Bertherat J, Allolio B, Fassnacht M. High diagnostic and prognostic value of steroidogenic factor-1 expression in adrenal tumors. J Clin Endocrinol Metab 2010; 95: E161-E171
    CrossrefPubMedGoogle Scholar
  • 8 Almeida MQ, Soares IC, Ribeiro TC, Fragoso MC, Marins LV, Wakamatsu A, Ressio RA, Nishi MY, Jorge AA, Lerario AM, Alves VA, Mendonca BB, Latronico AC. Steroidogenic factor 1 overexpression and gene amplification are more frequent in adrenocortical tumors from children than from adults. J Clin Endocrinol Metab 2010; 95: 1458-1462
    CrossrefPubMedGoogle Scholar
  • 9 Figueiredo BC, Cavalli LR, Pianovski MA, Lalli E, Sandrini R, Ribeiro RC, Zambetti G, DeLacerda L, Rodrigues GA, Haddad BR. Amplification of the steroidogenic factor 1 gene in childhood adrenocortical tumors. J Clin Endocrinol Metab 2005; 90: 615-619
    CrossrefPubMedGoogle Scholar
  • 10 Niakan KK, Davis EC, Clipsham RC, Jiang M, Dehart DB, Sulik KK, McCabe ER. Novel role for the orphan nuclear receptor Dax1 in embryogenesis, different from steroidogenesis. Mol Genet Metab 2006; 88: 261-271
    CrossrefPubMedGoogle Scholar
  • 11 Glover CH, Marin M, Eaves CJ, Helgason CD, Piret JM, Bryan J. Meta-analysis of differentiating mouse embryonic stem cell gene expression kinetics reveals early change of a small gene set. PLoS Comput Biol 2006; 2: e158
    CrossrefPubMedGoogle Scholar
  • 12 Khalfallah O, Rouleau M, Barbry P, Bardoni B, Lalli E. Dax-1 knockdown in mouse embryonic stem cells induces loss of pluripotency and multilineage differentiation. Stem Cells 2009; 27: 1529-1537
    CrossrefPubMedGoogle Scholar
  • 13 Kinsey M, Smith R, Iyer AK, McCabe ER, Lessnick SL. EWS/FLI and its downstream target NR0B1 interact directly to modulate transcription and oncogenesis in Ewing’s sarcoma. Cancer Res 2009; 69: 9047-9055
    CrossrefPubMedGoogle Scholar
  • 14 Reincke M, Beuschlein F, Lalli E, Arlt W, Vay S, Sassone-Corsi P, Allolio B. DAX-1 expression in human adrenocortical neoplasms: implications for steroidogenesis. J Clin Endocrinol Metab 1998; 83: 2597-2600
    CrossrefPubMedGoogle Scholar
  • 15 Shibata H, Ikeda Y, Mukai T, Morohashi K, Kurihara I, Ando T, Suzuki T, Kobayashi S, Murai M, Saito I, Saruta T. Expression profiles of COUP-TF, DAX-1, and SF-1 in the human adrenal gland and adrenocortical tumors: possible implications in steroidogenesis. Mol Genet Metab 2001; 74: 206-216
    CrossrefPubMedGoogle Scholar
  • 16 Bassett MH, Mayhew B, Rehman K, White PC, Mantero F, Arnaldi G, Stewart PM, Bujalska I, Rainey WE. Expression profiles for steroidogenic enzymes in adrenocortical disease. J Clin Endocrinol Metab 2005; 90: 5446-5455
    CrossrefPubMedGoogle Scholar
  • 17 Wieneke JA, Thompson LD, Heffess CS. Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 2003; 27: 867-881
    CrossrefPubMedGoogle Scholar
  • 18 Faria AM, Almeida MQ. Differences in the molecular mechanisms of adrenocortical tumorigenesis between children and adults. Mol Cell Endocrinol 2012; 351: 52-57
    CrossrefPubMedGoogle Scholar
  • 19 Fassnacht M, Johanssen S, Quinkler M, Bucsky P, Willenberg HS, Beuschlein F, Terzolo M, Mueller HH, Hahner S, Allolio B. Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer 2009; 115: 243-250
    CrossrefPubMedGoogle Scholar
  • 20 Helguero LA, Hedengran Faulds M, Forster C, Gustafsson JA, Haldosen LA. DAX-1 expression is regulated during mammary epithelial cell differentiation. Endocrinology 2006; 147: 3249-3259
    CrossrefPubMedGoogle Scholar
  • 21 Conde I, Alfaro JM, Fraile B, Ruiz A, Paniagua R, Arenas MI. DAX-1 expression in human breast cancer: comparison with estrogen receptors ER-alpha, ER-beta and androgen receptor status. Breast Cancer Res 2004; 6: R140-R148
    CrossrefPubMedGoogle Scholar
  • 22 Olaussen KA, Dunant A, Fouret P, Brambilla E, Andre F, Haddad V, Taranchon E, Filipits M, Pirker R, Popper HH, Stahel R, Sabatier L, Pignon JP, Tursz T, Le Chevalier T, Soria JC. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006; 355: 983-991
    CrossrefPubMedGoogle Scholar
  • 23 Almeida MQ, Fragoso MC, Lotfi CF, Santos MG, Nishi MY, Costa MH, Lerario AM, Maciel CC, Mattos GE, Jorge AA, Mendonca BB, Latronico AC. Expression of insulin-like growth factor-II and its receptor in pediatric and adult adrenocortical tumors. J Clin Endocrinol Metab 2008; 93: 3524-3531
    CrossrefPubMedGoogle Scholar
  • 24 Burris TP, Guo W, Le T, McCabe ER. Identification of a putative steroidogenic factor-1 response element in the DAX-1 promoter. Biochem Biophys Res Commun 1995; 214: 576-581
    CrossrefPubMedGoogle Scholar
  • 25 Vilain E, Guo W, Zhang YH, McCabe ER. DAX1 gene expression upregulated by steroidogenic factor 1 in an adrenocortical carcinoma cell line. Biochem Mol Med 1997; 61: 1-8
    CrossrefPubMedGoogle Scholar
  • 26 Park SY, Meeks JJ, Raverot G, Pfaff LE, Weiss J, Hammer GD, Jameson JL. Nuclear receptors Sf1 and Dax1 function cooperatively to mediate somatic cell differentiation during testis development. Development 2005; 132: 2415-2423
    CrossrefPubMedGoogle Scholar
  • 27 Lalli E. Methodological pitfalls in the study of DAX-1 function. Cell Death Disease 2014; 5: e977
    CrossrefPubMedGoogle Scholar
  • 28 Tissier F, Cavard C, Groussin L, Perlemoine K, Fumey G, Hagnere AM, Rene-Corail F, Jullian E, Gicquel C, Bertagna X, Vacher-Lavenu MC, Perret C, Bertherat J. Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res 2005; 65: 7622-7627
    CrossrefPubMedGoogle Scholar
  • 29 Mizusaki H, Kawabe K, Mukai T, Ariyoshi E, Kasahara M, Yoshioka H, Swain A, Morohashi K. Dax-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1) gene transcription is regulated by wnt4 in the female developing gonad. Mol Endocrinol 2003; 17: 507-519
    CrossrefPubMedGoogle Scholar
  • 30 Giordano TJ, Kuick R, Else T, Gauger PG, Vinco M, Bauersfeld J, Sanders D, Thomas DG, Doherty G, Hammer G. Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling. Clin Cancer Res 2009; 15: 668-676
    CrossrefPubMedGoogle Scholar
  • 31 Lalli E, Alonso J. Targeting DAX-1 in embryonic stem cells and cancer. Expert Opin Ther Targets 14: 169-177
    PubMedGoogle Scholar
  • 32 Garcia-Aragoncillo E, Carrillo J, Lalli E, Agra N, Gomez-Lopez G, Pestana A, Alonso J. DAX1 a direct target of EWS/FLI1 oncoprotein, is a principal regulator of cell-cycle progression in Ewing’s tumor cells. Oncogene 2008; 27: 6034-6043
    CrossrefPubMedGoogle Scholar
  • 33 Oda T, Tian T, Inoue M, Ikeda J, Qiu Y, Okumura M, Aozasa K, Morii E. Tumorigenic role of orphan nuclear receptor NR0B1 in lung adenocarcinoma. Am J Pathol 2009; 175: 1235-1245
    CrossrefPubMedGoogle Scholar