Institute of Pathology, Ludwig-Maximilians-University (LMU), Munich, Germany.
Department of General, Visceral und Vascular Surgery, Friedrich-Schiller University, Jena, Germany.
J Clin Pathol. 2014 Jul;67(7):592-8. doi: 10.1136/jclinpath-2013-202106. Epub 2014 Apr 19.
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.
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.
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.
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.
p16(INK4a)是致癌过程中的一个重要因素，其表达与癌基因诱导的衰老有关。最近有研究表明，p16 的上调和下调表明结直肠锯齿状途径中的衰老障碍。然而，在软组织肉瘤（STS）中，衰老机制仍不清楚。在这项研究中，我们分析了一组特征明确的 STS 队列的 p16(INK4a)表达，并将结果与包括生存在内的临床病理参数相关联。
对 183 例软组织和骨肿瘤的组织微阵列（TMA）进行免疫组织化学分析。此外，在四个肉瘤细胞系中评估了 p16(INK4a)的 mRNA 表达，并通过用 5-氮杂-2′-脱氧胞苷处理进行去甲基化试验。
在未分化多形性肉瘤（UPS）中，p16(INK4a)蛋白表达为 69.1%，平滑肌肉瘤为 85.7%，滑膜肉瘤为 77.8%，脂肪肉瘤为 88.9%，血管肉瘤为 60.9%，恶性周围神经鞘瘤为 22.2%。在高级别肉瘤中观察到 p16(INK4a)的缺失，与患者生存降低显著相关（p=0.032）。在 DNA 水平上，四个肉瘤细胞系中的一个通过甲基化特异性 PCR 分析显示存在 p16(INK4a)启动子甲基化。使用 5-氮杂-2′-脱氧胞苷进行去甲基化后，p16(INK4a) mRNA 和蛋白表达得到恢复。
p16(INK4a)的上调可能与衰老的诱导有关，并表明存在衰老障碍。p16(INK4a)的下调发生在恶性进展中，与患者生存降低显著相关。p16(INK4a)的下调可能是由于肉瘤细胞中的 DNA 过度甲基化所致。
