Differential developmental expression of transcription factors GATA-4 and GATA-6, their cofactor FOG-2 and downstream target genes in testicular carcinoma in situ and germ cell tumors.
OBJECTIVE
Testicular germ cell cancer is the most common malignancy among young males. The pre-invasive precursor, carcinoma in situ testis (CIS), presumably originates from arrested and transformed fetal gonocytes. Given that GATA transcription factors have essential roles in embryonic and testicular development, we explored the expression of GATA-4, GATA-6, cofactor friend of GATA (FOG)-2, and downstream target genes during human testis development and addressed the question whether changes in this pathway may contribute to germ cell neoplasms.


METHODS
Fetal testis, testicular CIS, and overt tumor samples were analyzed by immunohistochemistry for GATA-4, GATA-6, FOG-2, steroidogenic factor 1 (NR5A1/SF1), anti-Müllerian hormone/Müllerian-inhibiting substance (AMH), and inhibin-alpha (INHalpha).


RESULTS
GATA-4 was not expressed in normal germ cells, except for a subset of gonocytes at the 15th gestational week. The CIS cells expressed GATA-4 and GATA-6 heterogeneously, whereas most of the CIS cells expressed GATA-4 cofactor FOG-2. GATA target gene SF-1 was expressed heterogeneously in CIS cells, whereas INHalpha and AMH were mostly negative. Seminomas and yolk sac tumors were positive for GATA-4 and GATA-6, but mostly negative for FOG-2 and the GATA target genes. In contrast, pluripotent embryonal carcinomas and choriocarcinomas were GATA-4 and GATA-6 negative.


CONCLUSIONS
Differential expression of the GATA-4 target genes suggested cell-specific functions of GATA-4 in the germ and somatic cells. The GATA-4 expression in early fetal gonocytes, CIS, and seminoma cells but the absence in more mature germ cells is consistent with the early fetal origin of CIS cells and suggests that GATA-4 is involved in early germ cell differentiation.
Salonen
Jonna
J
Institute of Biomedicine, Paediatric Research Center, Children's Hospital, University of Helsinki, Biomedicum Helsinki, PO Box 20, SF-00014 Helsinki, Finland.
Rajpert-De Meyts
Ewa
E
Mannisto
Susanna
S
Nielsen
John E
JE
Graem
Niels
N
Toppari
Jorma
J
Heikinheimo
Markku
M
D054304:Anti-Mullerian Hormone / Q000378:metabolism; D002278:Carcinoma in Situ / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050991:GATA4 Transcription Factor / Q000378:metabolism*; D050993:GATA6 Transcription Factor / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007265:Inhibins / Q000378:metabolism; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000378:metabolism*; D000072260:RNA Splicing Factors; D013736:Testicular Neoplasms / Q000378:metabolism*; D013737:Testis / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; D000072260:RNA Splicing Factors; C107467:SF1 protein, human; D014157:Transcription Factors; C117427:ZFPM2 protein, human; C422362:inhibin A; D007265:Inhibins; D054304:Anti-Mullerian Hormone