Expression of the PDGF α‐receptor 1.5 kb transcript, OCT‐4, and c‐KIT in human normal and malignant tissues. Implications for the early diagnosis of testicular germ cell tumours and for our understanding of regulatory mechanisms

Abstract

Human testicular germ cell tumours of adolescents and adults (TGCTs), including their precursor lesion carcinoma in situ (CIS), show expression of a 1.5 kb alternative transcript of the platelet-derived growth factor (PDGF) alpha-receptor gene. The so-called P2 promoter involved is located in intron 12 and its activity was found to be mutually exclusive with activity of the classical promoter (P1), which encodes the full-length receptor. The presence of the 1.5 kb transcript could be a putative marker for the early molecular diagnosis of TGCTs. In order to validate the RT-PCR approach, this study shows that not more than 100 transcripts are necessary to obtain positivity in the test used; moreover, samples from TGCTs or CIS-containing tissues can be diluted many-fold before resulting in false-negative findings. This study also shows that within TGCTs, as in TGCT-derived cell lines, expression of the 1.5 kb transcript is differentiation-dependent and positively correlated with expression of the embryonic transcription factor OCT-4/POU5F1. Furthermore, the results indicate that in some non-TGCT cancers and cell lines the 1.5 kb transcript is also expressed, but without concomitant OCT-4/POU5F1 expression. The 1.5 kb transcript is also present in early B cells and derived leukaemias (B-ALL). In spite of similarities in chromosomal location, down-regulation upon differentiation of TGCTs, and PDGF alpha-receptor and c-KIT (the stem cell factor receptor) both being a tyrosine kinase receptor, no correlation was found between activity of the P2 promoter of the PDGF alpha-receptor gene and expression of c-KIT. In conclusion, the 1.5 kb transcript of the PDGF alpha-receptor is expressed in various cells and tissues, including particular blood cells. Although this may hamper the use of this transcript as a marker for malignancies in general, it does not appear to interfere with assays for the early detection of TGCTs.

Stem cell pluripotency and transcription factor Oct4

“…These similarities suggest that some embryonic genes may be re-expressed or re-activated in cancer cells. Palumbo et al reported that human testicular germ cell tumors [TGCTs] express a 1.5kb alternative transcript of the platelet-derived growth factor (PDGF) alpha receptor gene [51]. Others have reported that Oct4 and three other novel embryonic genes are expressed in human tumors but not in normal somatic tissues [[52], in agreement with the hypothesis that embryonic genes are re-activated in tumor cells.…”

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

“…protein phosphatase or protein tyrosine phosphatases) and thereby contribute to the activation of ERK (Lee and Esselman, 2002) Another scenario may be that CDDP ligates growth factor receptors, thereby activating the MEK -ERK pathway, as suggested for the cervical carcinoma cell line HeLa (Wang et al, 2000). Indeed there are even some reports demonstrating that TGCT express an aberrant platelet-derived growth factor areceptor, which is hypothetically capable of activating the MEK -ERK pathway upon ligation (Kollmannsberger et al, 2002;Palumbo et al, 2002).…”

Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges

“…Considering that STAT5 is a possible downstream target of SRC (Drayer et al 2005), it will be important to determine whether it is activated via JAK2, SRC, or another pathway in gonocytes. The presence of a variant PDGFRA form in gonocytes is interesting in view of the existence of a similar variant transcript identified in seminomas, the most common type of TGCTs (Palumbo et al 2002), and because of the possible relationship between improper gonocyte development and TGCT formation (Rajpert-De Meyts & Hoei-Hansen 2007).…”