Elsevier

Oral Oncology

Volume 38, Issue 6, September 2002, Pages 549-556
Oral Oncology

Expression of cyclin D1 and GSK-3β and their predictive value of prognosis in squamous cell carcinomas of the tongue

https://doi.org/10.1016/S1368-8375(01)00121-XGet rights and content

Abstract

The status of cyclin D1 and glycogen synthase kinase 3β (GSK-3β) was investigated in 41 patients with T1 and T2 squamous cell carcinomas (SCCs) of the tongue. Out of the 41 SCCs, 27 (65.9%) showed overexpression of cyclin D1 in comparison with normal lingual epithelia by an immunohistochemical method. Cyclin D1 gene amplification was detected in only two (9.1%) of 22 informative cases of the SCCs by differential PCR. Expression of GSK-3β, which was found to regulate proteosomal degradation of cyclin D1 protein, was reduced in 16 cases (39.0%) of the SCCs relative to normal epithelia, and the intensity of GSK-3β staining showed an inverse association with cyclin D1. These findings suggest that overexpression of cyclin D1 primarily results from stabilization due to reduction of GSK-3β, but not cyclin D1 gene amplification, in lingual SCCs. Kaplan–Meier analysis demonstrated that the patients with high cyclin D1 and reduced GSK-3β expression had a significantly lower 5-year survival than the patients with low cyclin D1 and non-reduced GSK-3β expression (P=0.014). The cyclin D1 and GSK-3β coupled assessment was more valuable for the prediction of prognosis than assessment based on cyclin D1.

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).

Section snippets

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.

References (30)

  • J.A Diehl et al.

    Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization

    Genes Dev

    (1998)
  • D Ramljak et al.

    A potential mechanism for fumonisin B1-mediated hepatocarcinogenesis: cyclin D1 stabilization associated with activation of Akt and inhibition of GSK-3β activity

    Carcinogenesis

    (2000)
  • L.H Sobin et al.

    TNM classification of malignant tumours. 5th ed

    (1997)
  • J.J Pindborg et al.

    Histological typing of cancer and precancer of the oral mucosa. 2nd ed

    (1997)
  • P.A Jakobsson et al.

    Histologic classification and grading of malignancy in carcinoma of the larynx

    Acta Radiol Ther Phys Biol.

    (1973)
  • Cited by (55)

    • The prognostic value of cyclin D1 expression in the survival of cancer patients: A meta-analysis

      2020, Gene
      Citation Excerpt :

      All analyses were completed using the comprehensive meta-analysis software version 2 (Biostat, Inc., Englewood, NJ) (Borenstein et al., 2005). An initial search retrieved 565 potentially relevant publications, and after checking eligibility and exerting inclusion and exclusion criteria, a total of 108 qualified articles remained for the final analysis (Kenny et al., 1999; Ortiz et al., 2017; Ahlin et al., 2017; Keum et al., 1999; Huang et al., 2012; Tut et al., 2001; Åkervall et al., 1997; Al-Kuraya et al., 2004; Anayama et al., 1998; Anton et al., 2000; Au et al., 2004; Bahnassy et al., 2004; Bhatavdekar et al., 2001; Bondi et al., 2005; Bonnefoi et al., 2003; Bova et al., 2001; Bukholm et al., 2001; Caputi et al., 1997; Chen et al., 2012; Choschzick et al., 2011; Dosaka-Akita et al., 2001; Dworakowska et al., 2005; Dworakowska et al., 2009; Elsheikh et al., 2008; Esposito et al., 2005; Fang et al., 2009; Feng et al., 2011; Fukuchi et al., 2006; Galmozzi et al., 2006; García et al., 2008; Goto et al., 2002; Grossi et al., 2010; Güner et al., 2003; Guo et al., 2007; Gupta et al., 2008; Hilska et al., 2005; Holland et al., 2001; Husdal et al., 2006; Hwang et al., 2003; Imamura et al., 2001; Jang et al., 2012; Jian-qun et al., 2004; Jin et al., 2001; Jiping et al., 2010; Jirström et al., 2005; Kawabuchi et al., 1999; Khoury et al., 2009; Kirkegaard et al., 2008; Kuo et al., 1999; Kuwahara et al., 1999; Kyomoto et al., 1997; Lee et al., 2007; Lee et al., 2010; Levidou et al., 2010; Li et al., 2014; Li et al., 2008; Liang et al., 2003; Lim, 2003; Lin et al., 2000; Lopez-Beltran et al., 2004; Lu et al., 2013; Lyall et al., 2006; Maeda et al., 1997; Mao et al., 2011; Massidda et al., 2010; McIntosh et al., 1995; McKay et al., 2002; Michalides et al., 1996; Millar et al., 2009; Mineta et al., 2000; Mishina et al., 1999; Moore et al., 2004; Mylona et al., 2013; Nagasawa et al., 2001; Nguyen et al., 2000; Nishio et al., 1997; Oba et al., 2011; Ogino et al., 2009; Palmqvist et al., 1998; Pelosio et al., 1996; Peurala et al., 2013; Ratschiller et al., 2003; Reis-Filho et al., 2006; Rodriguez et al., 2004; Rudas et al., 2008; Sánchez-Mora et al., 2008; Sarbia et al., 1999; Saridaki et al., 2010; Seiler et al., 2014; Seshadri et al., 1996; Sgambato et al., 2002; Shah et al., 2004; Shah et al., 2009; Shan et al., 2017; Shariat et al., 2010; Shinohara et al., 2002; Shiraki et al., 2005; Sterlacci et al., 2010; Takagi et al., 2000; Takano et al., 1999; Umekita et al., 2002; Utsumi et al., 2000; Van Diest et al., 1997; Vora et al., 2003; Wachter et al., 2013; Wang et al., 2012; Yu et al., 2005; Yurakh et al., 2006). These eligible articles were published between 1995 and 2017.

    • Clinicopathological significance of tumor cyclin D1 expression in oral cancer

      2019, Archives of Oral Biology
      Citation Excerpt :

      Tissue from an OSCC of known cyclin D1 and Ki67 expression served as positive control. No control group was used for cyclin D1 expression, given the well-documented and consistent negativity for cyclin D1 of healthy oral epithelia (Das, Khare, Singh, & Sharma, 2011; Goto, Kawano, Kobayashi, Sakai, & Yanagisawa, 2002; Kuo, Lin, Hahn, Cheng, & Chiang, 1999; Mishra & Das, 2009; Mishra, Nagini, & Rana, 2015; Wang et al., 2006; Wong et al., 2003; Zhang et al., 2015). Slides were digitalized using a Philips IntelliSite Ultra-Fast Scanner (Philips Digital Pathology Solutions, Best, The Netherlands), and the tumor expression of markers was evaluated in four randomly selected tumor fields of 0.191 mm2 (equivalent to 40x magnification) with the Philips IMS viewer (Philips Digital Pathology Solutions), which offers high magnification, definition, and reproducibility.

    • Asymmetrical proliferative pattern loss linked to cyclin D1 overexpression in adjacent non-tumour epithelium in oral squamous cell carcinoma

      2019, Archives of Oral Biology
      Citation Excerpt :

      Positive controls were OSCC tissues known to express cyclin D1 and Ki-67. There was no control group for cyclin D1 expression, widely reported to be negative in healthy oral tissue (Das, Khare, Singh, & Sharma, 2011; Goto, Kawano, Kobayashi, Sakai, & Yanagisawa, 2002; Kuo, Lin, Hahn, Cheng, & Chiang, 1999; Wang et al., 2006; Wong et al., 2003). All slides were digitalised using a Philips IntelliSite Ultra Fast Scanner (Philips Digital Pathology Solutions, Best, Netherlands).

    • Cell cycle-regulatory cyclins and their deregulation in oral cancer

      2013, Oral Oncology
      Citation Excerpt :

      Cyclin D1 turnover is regulated by IκB kinase alpha (IKKα [87], and this regulation occurs in oral carcinogenesis [88]. The accumulation of cyclin D1 in the nucleus is regulated by GSK3β inactivation, and this process is observed in OSCC [89]. The inactivated and phosphorylated GSK3β (Ser9 residue) forms are common in OSCC and have been reported in an animal model [90,91].

    View all citing articles on Scopus
    View full text