Abstract
Sirtuin 1 (SIRT1), a well-characterized NAD+-dependent histone deacetylase, is generally up-regulated in gastrointestinal cancers. However, the prognostic value of SIRT1 in gastrointestinal cancer remains inconclusive. Therefore, we report a meta-analysis of the association of SIRT1 expression with overall survival (OS) in gastrointestinal cancer. PubMed was systematically searched for studies evaluating the expression of SIRT1 and OS in patients with gastrointestinal cancer. Fifteen studies (six evaluating colorectal cancer, three evaluating hepatocellular carcinoma, three evaluating gastric cancer, and one each evaluating pancreatic cancer, esophageal squamous cell carcinoma, and gastroesophageal junction cancer) with 3,024 patients were finally included. The median percentage of gastrointestinal cancers with high SIRT1 expression was 52.5%. Overall analysis showed an association between high SIRT1 expression and worse OS [summary hazard ratio (sHR) 1.54, 95% confidence intervals (CI) 1.21-1.96] in gastrointestinal cancer. However, heterogeneity was observed across studies, which was mainly attributed to cancer type. Subgroup analysis revealed that SIRT1 was significantly associated with worse OS in non-colorectal gastrointestinal cancer (sHR 1.82, 95% CI 1.50-2.21), in particular in gastric cancer (sHR 3.19, 95% CI 1.97-5.16) and hepatocellular carcinoma (sHR 1.53, 95% CI 1.16-2.01), with no evidence of heterogeneity or bias. However, no association was observed in colorectal cancer (sHR 1.15, 95% CI 0.81-1.62). In conclusion, high SIRT1 expression is a potential marker for poor survival in non-colorectal gastrointestinal cancer, but not in colorectal cancer.
Highlights
Cancers of the digestive system are among the most common types of malignant tumors worldwide [1]
Subgroup analysis revealed that Sirtuin 1 (SIRT1) was significantly associated with worse overall survival (OS) in noncolorectal gastrointestinal cancer, in particular in gastric cancer and hepatocellular carcinoma, with no evidence of heterogeneity or bias
For hepatocellular carcinoma (3 studies, 425 patients) and gastric cancer (3 studies, 318 patients), high SIRT1 expression was significantly associated with worse OS with no heterogeneity (Table 3)
Summary
Cancers of the digestive system are among the most common types of malignant tumors worldwide [1]. Epigenetics is a promising field for prognostic biomarker research, because aberrant epigenetic modification underlies the formation and the progression of cancers Numerous studies in this field have linked histone deacetylases, which constitute one class of epigenetic regulators, to clinical outcomes and prognoses in cancer patients [2]. It was reported that transgenic SIRT1 expression promoted carcinogenesis in PTEN-deficient mice [8], whereas enterocyte-specific inactivation of SIRT1 reduced the tumor load in APC+/min mice [9]. These data have further argued for an in vivo tumor-promoting function of SIRT1 during cancer progression
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