Survival and Clinicopathological Significance of SIRT1 Expression in Cancers: A Meta-Analysis.

Peijie Lei,Heng Li,Sisi Xiong,Wenhua Zhang,Jin Zha,Dong Huang,Mengyu Du,Hongrui Zhu,Min Sun,Xinsheng Gu,Xingrui Gong

doi:10.3389/fendo.2019.00121

Peijie Lei, Heng Li + Show 9 more

Open Access

https://doi.org/10.3389/fendo.2019.00121

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Abstract

Background: Silent information regulator 2 homolog 1 (SIRT1) is an evolutionarily conserved enzymes with nicotinamide adenine dinucleotide (NAD)+-dependent deacetylase activity. SIRT1 is involved in a large variety of cellular processes, such as genomic stability, energy metabolism, senescence, gene transcription, and oxidative stress. SIRT1 has long been recognized as both a tumor promoter and tumor suppressor. Its prognostic role in cancers remains controversial.Methods: A meta-analysis of 13,138 subjects in 63 articles from PubMed, EMBASE, and Cochrane Library was performed to evaluate survival and clinicopathological significance of SIRT1 expression in various cancers.Results: The pooled results of meta-analysis showed that elevated expression of SIRT1 implies a poor overall survival (OS) of cancer patients [Hazard Ratio (HR) = 1.566, 95% CI: 1.293–1.895, P < 0.0001], disease free survival (DFS) (HR = 1.631, 95% CI: 1.250–2.130, P = 0.0003), event free survival (EFS) (HR = 2.534, 95% CI: 1.602–4.009, P = 0.0001), and progress-free survival (PFS) (HR = 3.325 95% CI: 2.762–4.003, P < 0.0001). Elevated SIRT1 level was associated with tumor stage [Relative Risk (RR) = 1.299, 95% CI: 1.114–1.514, P = 0.0008], lymph node metastasis (RR = 1.172, 95% CI: 1.010–1.360, P = 0.0363), and distant metastasis (RR = 1.562, 95% CI: 1.022–2.387, P = 0.0392). Meta-regression and subgroup analysis revealed that ethnic background has influence on the role of SIRT1 expression in predicting survival and clinicopathological characteristics of cancers. Overexpression of SIRT1 predicted a worse OS and higher TNM stage and lymphatic metastasis in Asian population especially in China.Conclusion: Our data suggested that elevated expression of SIRT1 predicted a poor OS, DFS, EFS, PFS, but not for recurrence-free survival (RFS) and cancer-specific survival (CCS). SIRT1 overexpression was associated with higher tumor stage, lymph node metastasis, and distant metastasis. SIRT1-mediated molecular events and biological processes could be an underlying mechanism for metastasis and SIRT1 is a therapeutic target for inhibiting metastasis, leading to good prognosis.

Highlights

Silent information regulator 2 homolog 1 (SIRT1) is an evolutionarily conserved enzymes with nicotinamide adenine dinucleotide (NAD)+-dependent deacetylase activity and a member of the mammalian sirtuin family
Studies enrolled in this analysis satisfied the following requirements: (i) patients must be diagnosed with cancer via pathology; (ii) The expression of Silent information regulator homolog 1 (SIRT1) must be determined by quantitative real-time polymerase chain reaction (q-PCR), immunohistochemistry (IHC), or in situ hybridization (ISH); (iii) The correlation between SIRT1 expression and prognosis or clinicopathological features was investigated; (iv) The Hazard Ratio (HR) and its 95% confidence interval (CI) for survival indicator on the basis of SIRT1 expression level were readily available or could be calculated indirectly; (v) The most representative and most accurate study was adopted when a single sample source was used in multiple studies to avoid unnecessary cohort overlapping
The results showed that SIRT1 overexpression was associated with a higher TNM stage (n = 17, relative risk (RR): 1.638, 95% CI: [1.404, 1.911], P < 0.0001, I2 = 41.16%) (Supplementary Figure 4B) and lymphatic metastasis in China (n = 11, RR: 1.411, 95% CI: [1.155, 1.724], P = 0.0007, I2 = 68.48%), and not with lymphatic metastasis in Japan (n = 3, RR: 0.964, 95% CI: [0.657, 1.415]), or Korea (n = 12, RR: 1.166, 95% CI: [0.898, 1.516]) (Supplementary Figure 6A)

Summary

Introduction

Silent information regulator 2 homolog 1 (SIRT1) is an evolutionarily conserved enzymes with nicotinamide adenine dinucleotide (NAD)+-dependent deacetylase activity and a member of the mammalian sirtuin family. It is expressed in almost all human tissues and localized in both nuclei and cytoplasm [1]. Silent information regulator 2 homolog 1 (SIRT1) is an evolutionarily conserved enzymes with nicotinamide adenine dinucleotide (NAD)+-dependent deacetylase activity. SIRT1 is involved in a large variety of cellular processes, such as genomic stability, energy metabolism, senescence, gene transcription, and oxidative stress.

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