Molecular changes associated with oral dysplasia progression and acquisition of immortality: Potential for its reversal by 5-azacytidine

Harrison, P., Muntoni, A., McGregor, F., Fleming, J., Brown, J. , Hunter, K., Gordon, K. and Parkinson, K. (2002) Molecular changes associated with oral dysplasia progression and acquisition of immortality: Potential for its reversal by 5-azacytidine. Cancer Research, 62(16), pp. 4757-4766.

Abstract

This study has identified molecular changes characteristic of early oral cancer progression. We reported previously that acquisition of the immortal phenotype is an early event in oral cancer development (F. McGregor et al., Cancer Res., 57: 3886–3889, 1997); our current data indicate that about half of oral dysplasia cultures are immortal, and this is associated with loss of expression of retinoic acid receptor (RAR)-ß and the cell cycle inhibitor p16ink4a (p16), p53 mutations, and increased levels of telomerase/human telomerase reverse transcriptase mRNA. In contrast, increased expression of the epidermal growth factor receptor, known to be a characteristic of oral cancer, does not occur until after the dysplasia stage in squamous cell carcinomas. Acquisition of invasive properties as judged by an in vitro Matrigel invasion assay also does not occur until the carcinoma stage and is further increased in metastases. Interestingly, one atypical mortal dysplasia with a considerably extended life span has lost expression of RAR-ß and p16, but it still expresses only wild-type p53 (albeit at a higher level than normal) and has not activated telomerase. RAR-ß and/or p16 re-expression can be induced by treatment with 5-aza-2-deoxycytidine (Aza-C) in some immortal dysplasias, and this has been shown to be due to silencing of gene expression by promoter methylation. Aza-C treatment also down-regulated telomerase activity and human telomerase reverse transcriptase mRNA. Interestingly, with one dysplasia, Aza-C was able to reverse its immortal phenotype, as judged by morphological criteria and expression of the senescence-associated acid ß-galactosidase activity during terminal growth arrest; this immortal dysplasia was the only one in which Aza-C treatment not only down-regulated telomerase activity but also induced re-expression of both RAR-ß and p16. The possibility of reversing the immortal phenotype of some dysplasias by Aza-C may be of clinical usefulness.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Brown, Dr Judith and Gordon, Mrs Karen and Hunter, Dr Keith and Harrison, Dr Paul
• Authors: Harrison, P., Muntoni, A., McGregor, F., Fleming, J., Brown, J., Hunter, K., Gordon, K., and Parkinson, K.
• Subjects: R Medicine > RK Dentistry
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Public Health; College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Dental School
• Journal Name: Cancer Research
• ISSN: 0008-5472