Loss of p16(INK4a) is associated with reduced patient survival in soft tissue tumours, and indicates a senescence barrier

Abstract

Aims p16(INK4a) is an important factor in carcinogenesis, and its expression is linked to oncogeneinduced 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 0 -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 0 -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 DNAhypermethylation in sarcoma cells.

Hypermethylation of potential tumor suppressor miR-34b/c is correlated with late clinical stage in patients with soft tissue sarcomas

“…Existing studies have shown various STS-susceptible genes, such as BMP2 and ASS1 genes, with abnormal DNA methylation in STSs, and the methylation changes may be associated with the progression and prognosis of STSs (Huang et al, 2013;Wolf et al, 2014). Another study suggested that p16 (INK4a) mRNA and protein expression downregulation due to hypermethylation of p16 (INK4a) promoter were observed in malignant progression within STSs and were associated with reduced patient survival (Knosel et al, 2014). In this study, we found aberrant miR-34b/c methylation occurs in STSs, we further investigated the possible associations between aberrant methylation and clinical characteristics.…”

Uterine leiomyosarcoma: a review of recent advances in molecular biology, clinical management and outcome

“…P16 is a tumour suppressor protein within the retinoblastoma (Rb) pathway that mediates the G1 to S transition in the cell cycle by binding cyclin‐dependent kinase CDK4‐cyclin D complex to act as a negative cell cycle regulator. A recent study examining the expression of p16 in soft tissue sarcomas found that upregulation of p16 in LMS may be associated with tumour senescence and significantly higher survival rates compared with p16 negative tumours …”

Cell-Cell Communication in the Tumor Microenvironment, Carcinogenesis, and Anticancer Treatment

“…One of the possible pathways by which cells communicate was seen when human melanoma cells (WM9), were exposed to simvastatin, which activated the p53/p21 pathway and induced a G1 arrest (senescent phenotype) and their intracellular ROS increased, as well [98]. On the other hand, an element upstream of p16(INK4a) seems to regulate the induction of senescence, as, in soft tissue and bone cancers, its downregulation is associated with tumor progression and reduced patient survival [99]. Connexin-43 (Cx43)-deficient hematopoietic stem cells (HSCs) exhibit an increased senescence that is dependent on their ability to transfer ROS to the hematopoietic microenvironment, and ROS accumulate in the HSCs.…”