Seladin‐1 and testicular germ cell tumours: new insights into cisplatin responsiveness

Abstract

The molecular basis for the exquisite sensitivity of testicular germ cell tumours of adolescents and adults (TGCTs), ie seminomas and non-seminomatous germ cell tumours, to chemo/radiotherapy has not been fully clarified so far. It has been suggested that it may be dependent on factors involved in the regulation of apoptosis. Seladin-1 is a multi-functional protein involved in various biological processes, including apoptosis. The aim of our study was to assess the expression of seladin-1 in different histological types of TGCTs, known to have varying treatment sensitivity, in order to establish whether this protein may influence cisplatin responsiveness in vitro. Seladin-1 expression levels, both at the mRNA and at the protein level, were higher in the adjacent normal parenchyma than in the pathological counterparts. In tumoural tissues, the level of expression differed among TGCT histological types. The highest tumour-expression level was found in teratoma, whereas the lowest was detected in seminoma, corresponding to the different chemo/and radiosensitivities of these tumour types. In common with other cancers, in TGCT-derived cell lines seladin-1 showed anti-apoptotic properties through inhibition of caspase-3 activation. We confirmed our results using a non-seminomatous cell line model (NT2) before and after differentiation with retinoic acid. Significantly higher seladin-1 expression was observed in the differentiated derivatives (teratoma) and an inverse relationship was found between seladin-1 expression and the amount of cleaved caspase-3. Seladin-1 silencing or overexpression in this cell line supports involvement of seladin-1 in cisplatin responsiveness. Seladin-1 silencing was associated with greater cisplatin responsiveness demonstrated by decreased cell viability and increased expression of apoptotic markers. In contrast, overexpression of seladin-1 was associated with a higher survival rate and a clear anti-apoptotic effect. In conclusion, we have demonstrated for the first time an important role for seladin-1 in the biology of TGCTs and provided new insights into cisplatin responsiveness of these tumours.

Promoter analysis of the DHCR24 (3β-hydroxysterol Δ24-reductase) gene: characterization of SREBP (sterol-regulatoryelement-binding protein)-mediated activation

“…DHCR24 expression has been reported to be altered in different tumours, such as adrenal gland, ovary, testis and prostate tumours [10–15,41]. The increase in DHCR24 expression by KLF5 may have a role in these alterations, since this transcription factor regulates proliferation, cell cycle, survival, migration, angiogenesis, apoptosis, differentiation and stemness [42].…”

Dissecting the molecular pathways of (testicular) germ cell tumour pathogenesis; from initiation to treatment‐resistance

“…These include for example XPA (Koberle et al, 1999(Koberle et al, , 2008Mayer et al, 2001;Welsh et al, 2004;Cummings et al, 2006), SRPK1 (Schenk et al, 2001(Schenk et al, , 2004, LRP, BAX, BCL2 etc. (Mayer et al, 2003a,b), seladin-1 (Nuti et al, 2009), CCND1 (Noel et al, 2010), P53 and MDM2 Burger et al, 1999;Kersemaekers et al, 2002;Mayer et al, 2002b;Bauer et al, 2010), cellular localization of p21 , the latter specifically investigated in embryonal carcinoma elements. In addition, genomic amplifications have been proposed to be involved (Rao et al, 1998).…”

The Association of CCND1 Overexpression and Cisplatin Resistance in Testicular Germ Cell Tumors and Other Cancers

“…17 Seladin-1, a multifunctional protein, has also recently been identified as a putative player in cisplatin sensitivity of TGCTs. 18 Since these resistance mechanisms only account for a limited proportion of the resistant cases, further studies are required. In this study, we performed a genome-wide gene expression analysis of three pairs of TGCT parental and resistant cell lines and identified CCND1 (Cyclin D1) overexpression in the three resistant lines.…”