Elevated levels and distinct patterns of expression of A‐type cyclins and their associated cyclin‐dependent kinases in male germ cell tumors

Abstract

Aberrant expression of several key regulators controlling the G1/S phase of the cell cycle has been implicated in human male germ cell tumorigenesis. Given the critical role of cyclin A2 at both the G1/S and G2/M transitions and the essential role for cyclin A1 in male germ cell development, our present study focused on the involvement of the A-type cyclins in the transformation and progression of male germ cell tumors (GCTs). The expression of the A-type cyclins and their catalytic partners Cdk1 and Cdk2 was examined in all types and stages of human male GCTs, including carcinoma in situ-(CIS), seminoma and non-seminoma GCTs, along with normal testis samples. Elevated levels of cyclin A2, Cdk1 and Cdk2 were detected in the majority of GCTs and were correlated with the invasiveness of the tumors (p < 0.05). Cyclin A1 expression was virtually undetectable in CIS and seminoma, but was aberrantly expressed in all non-seminomatous GCTs. Cyclin A2 expression was strongly correlated with that of its catalytic partners Cdk1 and Cdk2 in all types of testicular tumors examined (p < 0.05), whereas a strong correlation between cyclin A1 and Cdk1 or Cdk2 was only seen in non-seminomatous GCTs (p < 0.05). Histone kinase activities of cyclin A1/Cdks and cyclin A2/Cdks were found to be elevated in tumors. Our data suggest that aberrant expression of A-type cyclins and their Cdks is a significant factor in male germ cell tumorigenesis. The abundant ectopic expression of cyclin A1 in non-seminomatous GCTs and its absence in CIS and seminomas is likely linked to the tumor transformation and progression and may be relevant to clinical prognosis. Human testicular germ cell tumors (GCTs) are the most common malignancies occurring in the young male population and their frequency is increasing. 1-3 The tumors can be divided histologically into 2 primary categories, seminomas and non-seminomas. Seminomas account for half of all GCTs and retain the morphology of undifferentiated germ cells. 2 Non-seminomatous GCTs are further subdivided according to the degree of differentiation, with embryonal carcinoma exhibiting the most primitive pattern and teratoma the most mature type of differentiation along diverse lineages. 4 This class also includes extra-embryonally differentiated phenotypes such as choriocarcinoma and yolk-sac carcinoma. 2 GCTs of all types are frequently associated with carcinoma in situ (CIS), also designated as male germ cell neoplasia, which progresses to invasive lesions. 5 Both seminomatous and non-seminomatous GCTs have been suggested to arise from cytologically identical CIS lesions, indicating a common cell of origin of all GCTs. 2 Although several risk factors for GCT development have been identified, which include cryptorchidism, spermatogenic or testicular dysgenesis and possible family inheritance, the molecular mechanisms underlying the pathogenesis of GCTs are poorly understood.Cellular differentiation and proliferation is governed by the cell cycle machinery and involves progression through well-defined tran...

A role for cyclin A1 in mediating the autocrine expression of vascular endothelial growth factor in prostate cancer

“…Expression of cyclin A1, VEGF and PSA in patient samples on TMAs were assessed by immunohistochemical analysis using a semiautomatic diagnostic system (Ventana ES, Ventana Inc., Tucson, AZ, USA) as previously described (Liao et al, 2004). The specimens were viewed with an Olympus BX51 microscope.…”

“…In male germ cells, cyclin A1 is absolutely required for the meiotic division as demonstrated by gene-targeting (Liu et al, 1998). Further, elevated levels of cyclin A1 expression have been detected and shown to be associated with formation and progression in male germ cell tumors (CGTs) (Muller-Tidow et al, 2003;Liao et al, 2004).…”

A small molecule based on the pRb2/p130 spacer domain leads to inhibition of cdk2 activity, cell cycle arrest and tumor growth reduction in vivo

“…Cdk2 activity is regulated by several mechanisms, such as binding of cdk inhibitors like p21 waf1 , p27 Kip1 and p57 Kip2 (Malumbres and Barbacid, 2005), temporal association with cyclins A and E as well as phosphorylation of specific threonine and tyrosine residues (Gu et al, 1992). Constitutive activation of cyclin E/cdk2 complexes has been often associated with G 1 /S deregulation and tumor progression (Harwell et al, 2004;Liao et al, 2004;Sunters et al, 2004). Among the target substrates that cdks phosphorylate are the members of the retinoblastoma (Rb) family proteins, which play a pivotal role as negative regulators of cell cycle progression (Claudio et al, 1994;Caputi et al, 2005;Gallo and Giordano, 2005).…”

Tumor suppressor pRb2/p130 gene and its derived product Spa310 spacer domain as perspective candidates for cancer therapy

“…Several factors come into play in the regulation of cdk2 activity, such as binding of cdk2 inhibitors as p21 waf1 , p27 Kip1 , and p57 Kip2 (Malumbers and Barbacid, 2005), the already mentioned transient associations with cyclins A and E (Giordano et al, 1989(Giordano et al, , 1991Koff et al, 1992;Bates et al, 1994) and phosphorylation of specific tyrosine and threonine residues (Gu et al, 1992). The constitutive activation of cdk2/cyclin E complexes is often associated with the deregulation of G1 to S transition and tumor progression (Fujii et al, 1998;Harwell et al, 2004;Ioachim et al, 2004;Liao et al, 2004;Sunters et al, 2004;Peschos et al, 2005;Tenderenda, 2005). On these grounds, the targeting of cdk2 activity can have important implications for the development of therapeutics for cancer treatment.…”