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SIRT3 & SIRT7: Potential Novel Biomarkers for Determining Outcome in Pancreatic Cancer Patients.

McGlynn LM, McCluney S, Jamieson NB, Thomson J, MacDonald AI, Oien K, Dickson EJ, Carter CR, McKay CJ, Shiels PG - PLoS ONE (2015)

Bottom Line: Statistical analyses determined if SIRT1-7 protein expression was associated with clinical parameters or outcome.Two sirtuin family members demonstrated significant associations with clinico-pathological parameters and patient outcome.Low levels of nuclear SIRT7 expression were also associated with an aggressive tumour phenotype and poorer outcome, as measured by disease-free and disease-specific survival time, 12 months post-diagnosis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.

ABSTRACT

Purpose: The sirtuin gene family has been linked with tumourigenesis, in both a tumour promoter and suppressor capacity. Information regarding the function of sirtuins in pancreatic cancer is sparse and equivocal. We undertook a novel study investigating SIRT1-7 protein expression in a cohort of pancreatic tumours. The aim of this study was to establish a protein expression profile for SIRT1-7 in pancreatic ductal adenocarcinomas (PDAC) and to determine if there were associations between SIRT1-7 expression, clinico-pathological parameters and patient outcome.

Material and methods: Immunohistochemical analysis of SIRT1-7 protein levels was undertaken in a tissue micro-array comprising 77 resected PDACs. Statistical analyses determined if SIRT1-7 protein expression was associated with clinical parameters or outcome.

Results: Two sirtuin family members demonstrated significant associations with clinico-pathological parameters and patient outcome. Low level SIRT3 expression in the tumour cytoplasm correlated with more aggressive tumours, and a shorter time to relapse and death, in the absence of chemotherapeutic intervention. Low levels of nuclear SIRT7 expression were also associated with an aggressive tumour phenotype and poorer outcome, as measured by disease-free and disease-specific survival time, 12 months post-diagnosis.

Conclusions: Our data suggests that SIRT3 and SIRT7 possess tumour suppressor properties in the context of pancreatic cancer. SIRT3 may also represent a novel predictive biomarker to determine which patients may or may not respond to chemotherapy. This study opens up an interesting avenue of investigation to potentially identify predictive biomarkers and novel therapeutic targets for pancreatic cancer, a disease that has seen no significant improvement in survival over the past 40 years.

No MeSH data available.


Related in: MedlinePlus

SIRT3 expression levels are associated with outcome in patients not receiving chemotherapy.Kaplan-Meier survival analyses, stratified by chemotherapy status, were performed. Patients who did not receive chemotherapy and expressed low levels of cytoplasmic SIRT3 in their tumours were more likely to (a) relapse quicker (p = 0.05 11.8 vs 30.7 months) and (b) die earlier (p = 0.014, 14.6 vs 34.7 months) than patients who expressed high levels of SIRT3. Conversely there was no significant difference in outcome as measured by (c) time to recurrence or (d) time to death in terms of SIRT3 expression in patients who received chemotherapy.
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pone.0131344.g003: SIRT3 expression levels are associated with outcome in patients not receiving chemotherapy.Kaplan-Meier survival analyses, stratified by chemotherapy status, were performed. Patients who did not receive chemotherapy and expressed low levels of cytoplasmic SIRT3 in their tumours were more likely to (a) relapse quicker (p = 0.05 11.8 vs 30.7 months) and (b) die earlier (p = 0.014, 14.6 vs 34.7 months) than patients who expressed high levels of SIRT3. Conversely there was no significant difference in outcome as measured by (c) time to recurrence or (d) time to death in terms of SIRT3 expression in patients who received chemotherapy.

Mentions: No significant relationships were found between SIRT3 tumour expression levels and patient survival and/or disease recurrence in the full patient cohort (n = 77). As SIRT3 has a direct role in regulating cellular metabolism, it was deemed appropriate to stratify patients according to their chemotherapy status, as metabolism and chemotherapy efficacy may be linked. It was noted that 43.1% (22/51) of patients who expressed low levels of SIRT3 and 56.8% (29/51) of patients who expressed high levels of SIRT3 did not receive chemotherapy. This stratified analysis revealed a significant survival difference between low and high SIRT3 cytoplasmic expression in those patients who did not receive chemotherapy (Fig 3). Patients presenting with low levels of cytoplasmic SIRT3 in their tumour had a significantly shorter time to recurrence than those with high levels of cytoplasmic SIRT3 (p = 0.05, mean recurrence time 11.8 vs 30.7 months, Fig 3A). Low levels of cytoplasmic SIRT3 were associated with a 1.95 times greater risk of earlier relapse (HR = 1.95 (0.98–3.84) p = 0.054). Multivariate analysis revealed that cytoplasmic SIRT3 (p = 0.062), lymph node status (p = 0.008) and tumour differentiation (p = 0.041) were independent of tumour stage and grade, in influencing disease-free survival. Furthermore, cytoplasmic SIRT3 also had a significant impact on disease-specific survival in patients not receiving chemotherapy; low levels of SIRT3 were associated with a shorter time to death (p = 0.014, mean survival 14.6 vs 34.7 months, Fig 3B). Patients with low levels of SIRT3 were 2.23 times more likely to die earlier than those with high levels of SIRT3 (HR = 2.23 (1.15–4.29), p = 0.016). Multivariate cox-regression analysis revealed that cytoplasmic SIRT3 (p = 0.02), lymph node status (p = 0.006) and tumour differentiation (p = 0.006) were independent of tumour grade and size, in influencing disease-specific survival. No significant difference in outcome (disease-free or disease-specific) in terms of SIRT3 expression was observed for those patients receiving chemotherapy (Fig 3C and 3D).


SIRT3 & SIRT7: Potential Novel Biomarkers for Determining Outcome in Pancreatic Cancer Patients.

McGlynn LM, McCluney S, Jamieson NB, Thomson J, MacDonald AI, Oien K, Dickson EJ, Carter CR, McKay CJ, Shiels PG - PLoS ONE (2015)

SIRT3 expression levels are associated with outcome in patients not receiving chemotherapy.Kaplan-Meier survival analyses, stratified by chemotherapy status, were performed. Patients who did not receive chemotherapy and expressed low levels of cytoplasmic SIRT3 in their tumours were more likely to (a) relapse quicker (p = 0.05 11.8 vs 30.7 months) and (b) die earlier (p = 0.014, 14.6 vs 34.7 months) than patients who expressed high levels of SIRT3. Conversely there was no significant difference in outcome as measured by (c) time to recurrence or (d) time to death in terms of SIRT3 expression in patients who received chemotherapy.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4487247&req=5

pone.0131344.g003: SIRT3 expression levels are associated with outcome in patients not receiving chemotherapy.Kaplan-Meier survival analyses, stratified by chemotherapy status, were performed. Patients who did not receive chemotherapy and expressed low levels of cytoplasmic SIRT3 in their tumours were more likely to (a) relapse quicker (p = 0.05 11.8 vs 30.7 months) and (b) die earlier (p = 0.014, 14.6 vs 34.7 months) than patients who expressed high levels of SIRT3. Conversely there was no significant difference in outcome as measured by (c) time to recurrence or (d) time to death in terms of SIRT3 expression in patients who received chemotherapy.
Mentions: No significant relationships were found between SIRT3 tumour expression levels and patient survival and/or disease recurrence in the full patient cohort (n = 77). As SIRT3 has a direct role in regulating cellular metabolism, it was deemed appropriate to stratify patients according to their chemotherapy status, as metabolism and chemotherapy efficacy may be linked. It was noted that 43.1% (22/51) of patients who expressed low levels of SIRT3 and 56.8% (29/51) of patients who expressed high levels of SIRT3 did not receive chemotherapy. This stratified analysis revealed a significant survival difference between low and high SIRT3 cytoplasmic expression in those patients who did not receive chemotherapy (Fig 3). Patients presenting with low levels of cytoplasmic SIRT3 in their tumour had a significantly shorter time to recurrence than those with high levels of cytoplasmic SIRT3 (p = 0.05, mean recurrence time 11.8 vs 30.7 months, Fig 3A). Low levels of cytoplasmic SIRT3 were associated with a 1.95 times greater risk of earlier relapse (HR = 1.95 (0.98–3.84) p = 0.054). Multivariate analysis revealed that cytoplasmic SIRT3 (p = 0.062), lymph node status (p = 0.008) and tumour differentiation (p = 0.041) were independent of tumour stage and grade, in influencing disease-free survival. Furthermore, cytoplasmic SIRT3 also had a significant impact on disease-specific survival in patients not receiving chemotherapy; low levels of SIRT3 were associated with a shorter time to death (p = 0.014, mean survival 14.6 vs 34.7 months, Fig 3B). Patients with low levels of SIRT3 were 2.23 times more likely to die earlier than those with high levels of SIRT3 (HR = 2.23 (1.15–4.29), p = 0.016). Multivariate cox-regression analysis revealed that cytoplasmic SIRT3 (p = 0.02), lymph node status (p = 0.006) and tumour differentiation (p = 0.006) were independent of tumour grade and size, in influencing disease-specific survival. No significant difference in outcome (disease-free or disease-specific) in terms of SIRT3 expression was observed for those patients receiving chemotherapy (Fig 3C and 3D).

Bottom Line: Statistical analyses determined if SIRT1-7 protein expression was associated with clinical parameters or outcome.Two sirtuin family members demonstrated significant associations with clinico-pathological parameters and patient outcome.Low levels of nuclear SIRT7 expression were also associated with an aggressive tumour phenotype and poorer outcome, as measured by disease-free and disease-specific survival time, 12 months post-diagnosis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.

ABSTRACT

Purpose: The sirtuin gene family has been linked with tumourigenesis, in both a tumour promoter and suppressor capacity. Information regarding the function of sirtuins in pancreatic cancer is sparse and equivocal. We undertook a novel study investigating SIRT1-7 protein expression in a cohort of pancreatic tumours. The aim of this study was to establish a protein expression profile for SIRT1-7 in pancreatic ductal adenocarcinomas (PDAC) and to determine if there were associations between SIRT1-7 expression, clinico-pathological parameters and patient outcome.

Material and methods: Immunohistochemical analysis of SIRT1-7 protein levels was undertaken in a tissue micro-array comprising 77 resected PDACs. Statistical analyses determined if SIRT1-7 protein expression was associated with clinical parameters or outcome.

Results: Two sirtuin family members demonstrated significant associations with clinico-pathological parameters and patient outcome. Low level SIRT3 expression in the tumour cytoplasm correlated with more aggressive tumours, and a shorter time to relapse and death, in the absence of chemotherapeutic intervention. Low levels of nuclear SIRT7 expression were also associated with an aggressive tumour phenotype and poorer outcome, as measured by disease-free and disease-specific survival time, 12 months post-diagnosis.

Conclusions: Our data suggests that SIRT3 and SIRT7 possess tumour suppressor properties in the context of pancreatic cancer. SIRT3 may also represent a novel predictive biomarker to determine which patients may or may not respond to chemotherapy. This study opens up an interesting avenue of investigation to potentially identify predictive biomarkers and novel therapeutic targets for pancreatic cancer, a disease that has seen no significant improvement in survival over the past 40 years.

No MeSH data available.


Related in: MedlinePlus