Abstract
BackgroundSnoN is an important regulator of the transforming growth factor beta (TGFβ) signalling pathway and has been shown to exhibit both tumour promotion and suppression activity.MethodsTo further explore the role of this complex molecule in colorectal tumorigenesis, we examined 52 paired normal and tumour colorectal specimens stratified by level of microsatellite instability; 18 with high-level microsatellite instability (MSI-H) and 34 microsatellite stable (MSS). SnoN transcript expression was quantitated by real-time PCR and analysed with respect to clinical indicators of prognosis.ResultsWithin the MSI-H subgroup, SnoN was commonly either up-regulated (6/18, 33%) or down-regulated (7/18, 39%). A significantly different distribution of SnoN expression was observed in MSS cancers compared with MSI-H (P ≤ 0.001). Whilst 17/34 (50%) of MSS tumours demonstrated up-regulation, none showed down-regulated expression. Within the MSI-H subgroup, up-regulation was significantly correlated with lack of repeat tract mutation in the TGFβRII gene (P ≤ 0.025), suggesting that SnoN is more frequently up-regulated in the presence of functional TGFβ signalling.ConclusionTogether these data support the notion that SnoN has both oncogenic and tumour suppressive properties depending on other genetic changes within the tumour, and that the MSI-H pathway of colorectal tumorigenesis presents an excellent model for the study of these opposing functions.
Highlights
SnoN is an important regulator of the transforming growth factor beta (TGFβ) signalling pathway and has been shown to exhibit both tumour promotion and suppression activity
SnoN is a member of the highly homologous Ski gene family [1], and can act as a repressor of the TGF-β signalling pathway through either SnoN homodimerisation or heterodimerisation with Ski [1,2,3,4,5,6]. This repression is mediated through binding of SnoN to SMAD proteins, which are responsible for the propagation of signals initiated by TGF-β ligand for the transcription of genes required for cell growth control and differentiation [1,4,7,8]
Since regulation of TGFβ signalling by SnoN involves a combination of proteolytic degradation and transcriptional up-regulation in addition to changes in copy number, we suggest that quantification of SnoN expression may be a more informative way to assess its role in colorectal tumour development
Summary
SnoN is an important regulator of the transforming growth factor beta (TGFβ) signalling pathway and has been shown to exhibit both tumour promotion and suppression activity. SnoN (ski-related novel gene) is a member of the highly homologous Ski gene family [1], and can act as a repressor of the TGF-β signalling pathway through either SnoN homodimerisation or heterodimerisation with Ski [1,2,3,4,5,6] This repression is mediated through binding of SnoN to SMAD proteins, which are responsible for the propagation of signals initiated by TGF-β ligand for the transcription of genes required for cell growth control and differentiation [1,4,7,8]. SnoN has been shown to suppress tumour growth both in a heterozygote mouse model of SnoN inactivation [9] and in human cells [10] These opposing functions have led to difficulty in interpreting the complex roles of SnoN in human malignancies. Since regulation of TGFβ signalling by SnoN involves a combination of proteolytic degradation and transcriptional up-regulation in addition to changes in copy number, we suggest that quantification of SnoN expression may be a more informative way to assess its role in colorectal tumour development
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