Transcription factor AP-2gamma is a developmentally regulated marker of testicular carcinoma in situ and germ cell tumors.
OBJECTIVE
Transcription factor activator protein-2gamma (TFAP2C, AP-2gamma) was reported previously in extraembryonic ectoderm and breast carcinomas but not in the testis. In our recent gene expression study we detected AP-2gamma in carcinoma in situ testis (CIS, or intratubular germ cell neoplasia), precursor of testicular germ cell tumors. In this study we aimed to investigate the expression pattern of AP-2gamma and to shed light on this factor in germ cell differentiation and the pathogenesis of germ cell neoplasia.


METHODS
We analyzed expression pattern of AP-2gamma at the RNA and protein level in normal human tissues and a panel of tumors and tumor-derived cell lines. In the gonads, we established the ontogeny of expression of AP-2gamma in normal and dysgenetic samples. We also investigated the regulation of AP-2gamma by steroids and retinoic acid.


RESULTS
We detected abundant AP-2gamma in testicular CIS and in testicular germ cell tumors of young adults and confirmed differential expression of AP-2gamma in somatic tumors. We found that AP-2gamma expression was regulated by retinoic acid in an embryonal carcinoma cell line (NT2). The investigation of ontogeny of AP-2gamma protein expression in fetal gonads revealed that it was confined to oogonia/gonocytes and was down-regulated with germ cell differentiation. In some prepubertal intersex cases, AP-2gamma was detected outside of the normal window of expression, probably marking neoplastic transformation of germ cells.


CONCLUSIONS
AP-2gamma is developmentally regulated and associated with the undifferentiated phenotype in germ cells. This transcription factor may be involved in self-renewal and survival of immature germ cells and tissue-specific stem cells. AP-2gamma is a novel marker of testicular CIS and CIS-derived tumors.
Hoei-Hansen
Christina E
CE
University Department of Growth and Reproduction, Rigshospitalet, Denmark. cehh@biobase.dk
Nielsen
John E
JE
Almstrup
Kristian
K
Sonne
Si Brask
SB
Graem
Niels
N
Skakkebaek
Niels E
NE
Leffers
Henrik
H
Rajpert-De Meyts
Ewa
E
D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor; D002278:Carcinoma in Situ / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D018237:Germinoma / Q000209:etiology / Q000378:metabolism; D006059:Gonadal Dysgenesis / Q000150:complications / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D013256:Steroids / Q000494:pharmacology; D013736:Testicular Neoplasms / Q000235:genetics / Q000378:metabolism*; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D013256:Steroids; C493679:TFAP2C protein, human; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D014212:Tretinoin