Transcription Factor AP-2γ Is a Developmentally Regulated Marker of Testicular Carcinoma In situ and Germ Cell Tumors

Abstract

Purpose: Transcription factor activator protein-2␥ (TFAP2C, AP-2␥) was reported previously in extraembryonic ectoderm and breast carcinomas but not in the testis. In our recent gene expression study we detected AP-2␥ 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-2␥ 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-2␥ 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-2␥ in normal and dysgenetic samples. We also investigated the regulation of AP-2␥ by steroids and retinoic acid.Results: We detected abundant AP-2␥ in testicular CIS and in testicular germ cell tumors of young adults and confirmed differential expression of AP-2␥ in somatic tumors. We found that AP-2␥ expression was regulated by retinoic acid in an embryonal carcinoma cell line (NT2). The investigation of ontogeny of AP-2␥ 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-2␥ was detected outside of the normal window of expression, probably marking neoplastic transformation of germ cells.Conclusions: AP-2␥ 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-2␥ is a novel marker of testicular CIS and CISderived tumors.

Translational repression of E2F1 mRNA in carcinoma in situ and normal testis correlates with expression of the miR-17-92 cluster

“…18 Here, we show that CIS cells also express the miR-17-92 cluster, thus supporting earlier speculation that expression of miR-17-92 could be important for stem cell maintenance in the embryo. 9 In conclusion, our results indicate that miRNA downregulation of E2F1 mRNA translation is part of the normal spermatogenesis, protecting meiotic cells from apoptosis as modeled in Figure 1u.…”

Genome-wide gene expression profiling of testicular carcinoma in situ progression into overt tumours

“…This is consistent with recent reports on widespread expression of transcripts from both strands in large parts of the human genome (Kapranov et al, 2002;Cawley et al, 2004), and we speculate that this feature may contribute to the heterogeneity of overt tumours -especially N-SEMs. Even protein expression has earlier been reported to be markedly heterogeneous in TGCTs, including CIS (Rajpert-De Meyts et al, 1996;LifschitzMercer et al, 2002;Hoei-Hansen et al, 2004b;Kato et al, 2004). It is, however, evident from the RT -PCR results shown in Figure 2 that by combining results from a range of different genes, a TGCT sample could be classified as a SEM or N-SEM.…”

“…The undifferentiated EC and EC-derived cell lines have been more thoroughly investigated. A number of proteins highly expressed in EC are related to pluripotency, for example, POU5F1 (OCT-4) and TFAP2C (Hoei-Hansen et al, 2004b), and are equally highly expressed in SEM. It is important to remember that the genes we have identified here are differentially expressed between both CIS, SEM and N-SEM.…”

Overexpression of TFAP2C in invasive breast cancer correlates with a poorer response to anti‐hormone therapy and reduced patient survival

“…High levels of AP-2γ were found in testicular cancer [18], germ cell tumours [18,19], advanced stages of ovarian cancer [20], and certain stages of melanoma [21]. In breast cancer, data mining of microarray expression studies has shown an association between high levels of TFAP2C mRNA and higher clinical grade and shorter survival times [17,22].…”