Expression of cyclin D1 and GSK-3β and their predictive value of prognosis in squamous cell carcinomas of the tongue
Introduction
Cyclin D1 plays a critical role in the transition from the G1 to S phase of the cell cycle [1]. Complexes of cyclin D1 and cyclin dependent kinase (CDK) 4 or 6 phosphorylate retinoblastoma (Rb) protein, release E2F transcription factors from Rb protein, and consequently, induce the transcription of target genes. Protein overexpression and gene amplification of cyclin D1 have been reported in various human tumors, including squamous cell carcinomas of the head and neck [1]. In addition, it has been found that cyclin D1 status is associated with tumor grade [2], [3], [4], lymph node metastasis [3], [4], [5] and survival rate [3], [4], [5], [6] in head and neck SCCs. Most of these studies examined SCCs of this region as a single tumor entity, even though it is known that the clinical behavior of head and neck SCCs is different at the various sites within this area [7]. Since studies on cyclin D1 status in cancers confined to one anatomical site of the oral cavity are limited [3], [5], [8], we conducted the present investigation to obtain more accurate information on the clinical importance of cyclin D1 overexpression in SCCs of the tongue.
Recent studies have reported that GSK-3β regulates proteosomal degradation of cyclin D1 protein [9] and overexpression of cyclin D1 results from loss of GSK-3β activity [10]. In the present study, we undertook immunohistochemical detection of cyclin D1 and GSK-3β and compared the expression of both proteins with clinicopathological factors in T1 and T2 lingual SCCs, and also examined the prevalence of cyclin D1 gene amplification in lingual SCCs with the differential polymerase chain reaction (PCR).
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Patients
The 41 patients with T1 and T2 SCCs of the tongue were used and retrieved from the cancer patient files from 1981 to 1998 of the Department of Maxillo-Facial Surgery, Oita Medical University. The patients consisted of 24 males and 17 females with the mean age of 59.6 years (range 22–82 years). Clinical staging was determined according to the UICC classification (1997) [11]. Histological differentiation and the histological structure of primary tumors were evaluated by the criteria of WHO (1997)
Immunohistochemistry of cyclin D1
Cyclin D1 was localized in the nucleus of the cells. In normal epithelia, weak or faint nuclear staining against the anti-cyclin D1 Ab was observed occasionally in parabasal cells (Fig. 1a). In lingual SCCs, cyclin D1 reaction varied in intensity among the tumors. Out of 41 SCCs, 27 (65.9%) showed abundant of cyclin D1, in which various numbers of strongly-positive tumor cells were identified more frequently than in normal epithelia. Cyclin D1-positive cells tended to be distributed in the
Discussion
Previous studies have demonstrated that cyclin D1 was localized in the nuclei of keratinocytes in the parabasal and basal cell layers of the mucosal epithelia of the oral cavity [8]. The percentage of cyclin D1-positive cells was reported to be 5.69% through all of the layers of oral mucosal epithelium [8], though the intensity of staining was usually weak. In head and neck SCCs, cyclin D1 protein was detected in the nuclei of tumor cells as definitely strong signals and previous studies
Acknowledgements
The authors thank Dr. Yutaka Shimada (Kyoto University, Japan) for a kind gift of two cell lines of esophageal squamous cell carcinoma, KYSE 70 and KYSE 790. We also thank Dr. Masahiko Mori for a critical review of the manuscript.
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