Aberrant expression of p27Kip1-interacting cell-cycle regulatory proteins in ovarian clear cell carcinomas and their precursors with special consideration of two distinct multistage clear cell carcinogenetic pathways

Department of Basic Pathology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin (Impact Factor: 2.65). 10/2009; 455(5):413-22. DOI: 10.1007/s00428-009-0844-5
Source: PubMed


We have previously reported that alterations of p27(Kip1)-interacting cell-cycle proteins frequently occur during the development of endometriosis-associated ovarian clear cell adenocarcinoma (CCA; Yamamoto et al., Histopathology in press, 20). However, CCA also occurs in association with clear cell adenofibroma (CCAF). In this study, the expressions of p27(Kip1)-interacting proteins, i.e., p27(Kip1), Skp2, Cks1, cyclin A, cyclin E, and the Ki-67 labeling index (LI), were analyzed in 25 CCAFs (11 benign and 14 borderline) and 15 CCAF-associated CCAs, and compared with the expression status of each protein in the 23 previously studied endometriosis-associated CCAs. Although aberrant expression of all p27(Kip1)-interacting proteins was more frequent in the CCAF-associated CCAs than in the benign CCAFs, statistical significance was found only for Cks1 overexpression. The frequencies of p27(Kip1) downregulation and overexpression of Skp2 and cyclin A were significantly lower in CCAF-associated than in endometriosis-associated CCAs (P < 0.05, respectively). The frequencies of p27(Kip1) downregulation and Skp2 overexpression in borderline CCAFs were significantly lower than those in atypical endometriosis components in endometriosis-associated CCAs (P < 0.05, respectively). Mean Ki-67 LI increased significantly through benign (4.9%) to borderline (11.1%) CCAF and to CCAF-associated CCA (30.6%), but the latter two values were significantly lower than those in atypical endometriosis (21.4%) and endometriosis-associated CCA (46.9%; P < 0.05, respectively). These data suggest that accumulated alterations of p27(Kip1)-interacting proteins may accelerate the development of CCAs regardless of their carcinogenetic pathways, but that tumor cells in the CCAF-associated pathway appear to show slower cell-cycle progression than those in the endometriosis-associated pathway, possibly accounting for the distinct clinicopathological features of the two CCA subtypes.

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    • "Cks1 has been implicated in development of oral squamous cell carcinoma [131–133], salivary gland tumors [106], esophageal carcinomas [80,134,135], gastric carcinoma [20,136], colorectal carcinoma [108], gall bladder carcinoma [137] and hepatocellular carcinoma [19, 138–142]. Similarly Cks1 is believed to play a role in development and progression of several other types of cancers such as endometrial cancer [143], ovarian tumors [144–147], prostate cancer [148], testicular cancer [149], non small cell lung carcinomas (NSCLC) [111,150], cutaneous squamous cell carcinoma [151], melanoma [15], urothelial carcinoma and renal cell carcinomas [152,153], glioblastoma and CNS tumors [154,155], head and neck carcinoma [156], fibrosarcoma [157], and myxofibrosarcoma [158]. In many of these studies there is often a distinct correlation between Cks1 expression and clinicopathologic features such as tumor grade, stage, metastasis, loss of tumor differentiation patient prognosis and cancer free survival. "
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    ABSTRACT: Deregulation of the cell cycle results in loss of normal control mechanisms that prevent aberrant cell proliferation and cancer progression. Regulation of the cell cycle is a highly complex process with many layers of control. One of these mechanisms involves timely degradation of CDK inhibitors (CKIs) like p27(Kip1) by the ubiquitin proteasomal system (UPS). Cks1 is a 9 kDa protein which is frequently overexpressed in different tumor subtypes, and has pleiotropic roles in cell cycle progression, many of which remain to be fully characterized. One well characterized molecular role of Cks1 is that of an essential adaptor that regulates p27(Kip1) abundance by facilitating its interaction with the SCF-Skp2 E3 ligase which appends ubiquitin to p27(Kip1) and targets it for degradation through the UPS. In addition, emerging research has uncovered p27(Kip1)-independent roles of Cks1 which have provided crucial insights into how it may be involved in cancer progression. We review here the structural features of Cks1 and their functional implications, and also some recently identified Cks1 roles and their involvement in breast and other cancers.
    Full-text · Article · Oct 2013 · Journal of Cancer Therapy
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    ABSTRACT: Background CKS1B is a member of the highly conserved cyclin kinase subunit 1 (CKS1) family that interacts with cyclin-dependent kinases and plays an important role in cell cycle progression. We and others have shown that CKS1B amplification located on chromosome 1q21 is an adverse prognostic factor in multiple myeloma (MM), but its relationship with CKS1B nuclear protein expression, is unclear. Here, we investigated 94 newly-diagnosed MM patients and correlated nuclear CKS1B protein immunoreactivity, 1q21 amplification status, p27(Kip1) expression and survival. DESIGN AND METHODS: The CKS1B and p27(Kip1) nuclear expressions were evaluated by immunohistochemistry (IHC) in decalcified, paraffin-embedded bone marrow biopsies from 94 MM patients. Clonal plasma cells of the bone marrow aspirates from the same cohort were examined for CKS1B gene status by interphase cytoplasmic fluorescence in situ hybridization (cIg-FISH). RESULTS: Of the 94 patients, FISH detected 1q21 amplification in 36 (38%) patients and immunohistochemistry (IHC) detected CKS1B protein expression in 37 (39%). Thirty-two (86%) of the 36 amplified (1q21) cases expressed CKS1B and 31 (84%) of the 37 CKS1B immunoreactive cases had amplified 1q21. 1q21 amplification and CKS1B protein expression were strongly correlated (P<0.0001). CKS1B protein expression was inversely correlated with p27(Kip1)immunostaining (P<0.0001) and was associated with a shorter overall survival (median 44.5 vs. 89.3 months, P<0.0001). Conclusions CKS1B IHC is a simple, rapid method that appears to predict 1q21 amplification and adverse outcome for risk stratification of MM.
    Full-text · Article · Apr 2010 · Haematologica
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