Abstract
The thioredoxin (Trx) system is an important enzyme family that regulates cellular redox homeostasis. Protein expression of Trx system family members has been assessed in various cancers and linked to various clinicopathological variables, disease progression, treatment response and survival outcomes but information is lacking in brain tumours. Expression of the system was therefore examined, by immunohistochemistry in different brain tumour types, adult and paediatric cases, to determine if expression was of importance to clinical outcome. Trx system proteins were expressed, to variable levels, across all brain tumour types with significant variations in expression between different tumour types/grades/regions. High Trx reductase (TrxR) expression was linked to worse prognosis across all cohorts. High cytoplasmic TrxR expression was significantly associated with adverse overall survival (OS) in adult glioblastoma (P = 0.027) and paediatric low-grade glioma (LGG) patients (P = 0.012). High expression of nuclear TrxR, cytoplasmic and nuclear Trx and Trx-interacting protein (TxNIP) was associated with improved OS in paediatric LGGs (P = 0.031, P < 0.001, P = 0.044 and P = 0.018, respectively). For patients with high-grade gliomas, both high cytoplasmic TrxR and Trx expression were associated with poor OS (P = 0.002 and P = 0.007, respectively). In medulloblastoma, high expression of cytoplasmic TrxR and Trx and nuclear Trx was associated with worse prognosis (P = 0.013, P = 0.033 and P = 0.007, respectively); with cytoplasmic TrxR and nuclear Trx remaining so in multivariate analysis (P = 0.009 and P = 0.013, respectively). The consistent finding that high levels of cytoplasmic TrxR are associated with a worse prognosis across all cohorts suggests that TrxR is an important therapeutic target in brain cancers.
Highlights
Gliomas are the most frequent type of primary brain tumours in both adults and children, with glioblastoma multiforme (GBM) being the most malignant and most common type in adults [1]
The current study investigated the expression of all three Trx system proteins in four independent brain tumour cohorts; and whether any associations existed between their expression and patient prognosis or with clinicopathological variables
Current survival data demonstrate that high cytoplasmic Trx reductase (TrxR) expression is significantly associated with adverse overall survival in adult GBMs (P = 0.027)
Summary
Gliomas are the most frequent type of primary brain tumours in both adults and children, with glioblastoma multiforme (GBM) being the most malignant and most common type in adults [1]. Despite advances in diagnosis and treatment, survival times have not significantly improved for malignant glioma patients, especially GBM patients, whose median survival time is only around 15 months from diagnosis with a 5-year survival rate of 6% [2]. Multimodal treatment strategies are used, 15–20% of the average-risk and 30–40% of the high-risk patients develop recurrences resulting in poor survival outcome [5]. The median survival after relapse is around 10 months [6] and the 5-year survival after relapse is 6% [7] Both malignant gliomas and MBs are highly invasive tumours, with recurrence after treatment almost inevitable, resulting in extremely poor prognosis. There is, a pressing need to identify reliable and robust prognostic biomarkers to better stratify patients in order to improve their survival and to identify novel targets for development of therapeutics
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