Loss of p16(INK4a) is associated with reduced patient survival in soft tissue tumours, and indicates a senescence barrier
Autor: | Gesa Schuebbe, Helge Siemens, Rolf D. Issels, Sebastian Gibis, Thomas Kirchner, Eric Kampmann, Thomas Knösel, Heiko Hermeking, Annelore Altendorf-Hofmann, Lars H. Lindner |
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Rok vydání: | 2014 |
Předmět: |
Adult
Male Senescence Pathology medicine.medical_specialty Down-Regulation Soft Tissue Neoplasms Kaplan-Meier Estimate Biology Undifferentiated Pleomorphic Sarcoma Pathology and Forensic Medicine Young Adult Downregulation and upregulation Risk Factors Cell Line Tumor Biomarkers Tumor medicine Humans RNA Messenger Promoter Regions Genetic neoplasms Cellular Senescence Cyclin-Dependent Kinase Inhibitor p16 Aged Aged 80 and over Tissue microarray Soft tissue sarcoma Sarcoma General Medicine DNA Methylation Middle Aged Prognosis medicine.disease Immunohistochemistry Synovial sarcoma Gene Expression Regulation Neoplastic body regions Tissue Array Analysis Cancer research Cell aging |
Zdroj: | Journal of Clinical Pathology. 67:592-598 |
ISSN: | 1472-4146 0021-9746 |
Popis: | Aims p16(INK4a) is an important factor in carcinogenesis, and its expression is linked to oncogene-induced senescence. Very recently it was shown that upregulation and downregulation of p16 indicates a senescence barrier in the serrated route of colorectal cancer. However, in soft tissue sarcoma (STS), the senescence mechanism is still not understood. In this study, we analysed a well characterised cohort of STS for p16(INK4a) expression and correlated the results with clinicopathological parameters including survival. Methods Tissue microarrays (TMA) of 183 soft tissue and bone tumours were analysed immunohistochemically. Furthermore, mRNA expression of p16(INK4a) was evaluated in four sarcoma cell lines, and a demethylation test was performed by treatment with 5-aza-2′-deoxycytide. Results On protein level, expression of p16(INK4a) was observed in undifferentiated pleomorphic sarcoma (UPS) in 69.1%, leiomyosarcoma in 85.7%, synovial sarcoma in 77.8%, liposarcoma in 88.9%, angiosarcoma in 60.9% and MPNST in 22.2%. Loss of p16(INK4a) was observed in high grade sarcomas and showed a significant correlation with reduced patient survival (p=0.032). On DNA level, one out of four sarcoma cell lines exhibited a methylated p16(INK4a) promoter analysed by methylation-specific PCR. p16(INK4a) mRNA and protein expression was restored after demethylation using 5-aza-2′-deoxycytide. Conclusions Upregulation of p16(INK4a) might be associated with the induction of senescence and indicates a senescence barrier. Downregulation of p16(INK4a) is found in malignant progression, and is significantly correlated with reduced patient survival. Downregulation of p16(INK4a) may be explained by DNA-hypermethylation in sarcoma cells. |
Databáze: | OpenAIRE |
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