TY - JOUR
T1 - Transcription factor AP-2gamma is a developmentally regulated marker of testicular carcinoma in situ and germ cell tumors
AU - Hoei-Hansen, Christina E
AU - Nielsen, John E
AU - Almstrup, Kristian
AU - Sonne, Si Brask
AU - Graem, Niels
AU - Skakkebaek, Niels E
AU - Leffers, Henrik
AU - Rajpert-De Meyts, Ewa
N1 - Keywords: Adolescent; Adult; Carcinoma in Situ; Cell Differentiation; Child; Child, Preschool; DNA-Binding Proteins; Female; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Germinoma; Gonadal Dysgenesis; Humans; Infant; Infant, Newborn; Male; Middle Aged; Ovarian Neoplasms; Pregnancy; Steroids; Testicular Neoplasms; Transcription Factor AP-2; Transcription Factors; Tretinoin; Tumor Markers, Biological
PY - 2004
Y1 - 2004
N2 - PURPOSE: 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. EXPERIMENTAL DESIGN: 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.
AB - PURPOSE: 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. EXPERIMENTAL DESIGN: 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.
U2 - 10.1158/1078-0432.CCR-04-1285
DO - 10.1158/1078-0432.CCR-04-1285
M3 - Journal article
C2 - 15623634
SN - 1078-0432
VL - 10
SP - 8521
EP - 8530
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -