Abstract
BackgroundIdentification of novel molecular biomarkers will improve the management of patients with gastric cancer (GC). Prenyl diphosphate synthase subunit 2 (PDSS2) is required for coenzyme Q10 biosynthesis and acts as a tumor suppressor; however, the role and regulatory mechanisms of PDSS2 in GC are not understood. The aim of this study was to determine expression status and regulatory mechanisms of PDSS2 in GC.MethodsAssociations between expression and methylation of PDSS2 were evaluated using GC cell lines. The clinical significance of PDSS2 expression was evaluated using 238 pairs of surgically resected gastric tissues with subgroup analysis based on GC subtypes.ResultsThe expression of PDSS2 mRNA was decreased in 73% of GC cell lines compared with the control non-cancerous cell. The PDSS2 promoter was hypermethylated in cells with decreased PDSS2 expression, and treating these cells with a methylation inhibitor reactivated PDSS2 expression. GC tissues expressed significantly lower mean levels of PDSS2 mRNA compared with adjacent normal tissues (P <0.001). The expression pattern of PDSS2 protein was consistent with that of its mRNA. The decrease of PDSS2 mRNA expression in GC tissues (less than half the level of expression detected in the corresponding normal adjacent tissues) correlated significantly with elevated levels of carbohydrate antigen 19-9 (P = 0.015), lymph node metastasis (P = 0.022), and shorter recurrence-free survival after curative resection (P = 0.022). Further, multivariate analysis identified PDSS2 mRNA expression as an independent prognostic factor (hazard ratio 1.95, 95% confidence interval 1.22–3.09, P = 0.005), and its expression pattern and prognostic significance were similar among three GC subtypes.ConclusionsPDSS2 encodes a putative tumor suppressor, and we show here that its expression was regulated by hypermethylation of its promoter in GC cells. Inhibition of PDSS2 mRNA expression may serve as a novel biomarker of all types of GC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-014-0088-3) contains supplementary material, which is available to authorized users.
Highlights
Identification of novel molecular biomarkers will improve the management of patients with gastric cancer (GC)
To evaluate whether the expression level of Prenyl diphosphate synthase subunit 2 (PDSS2) correlated with tumor phenotype, patients were categorized into three groups according to the definition of GC subtypes according to the criteria of Shah et al [9] as follows: proximal nondiffuse, diffuse, and distal nondiffuse type
We hypothesized that hypermethylation of the CpG islands regulates the expression of PDSS2 in GC
Summary
Identification of novel molecular biomarkers will improve the management of patients with gastric cancer (GC). Shah et al [9] proposed a convincing classification of GC according to histopathologic and anatomic criteria as follows: (1) proximal nondiffuse GC where the tumor is located mainly in the gastric cardia with evidence of precursor glandular dysplasia or in situ carcinoma in the presence of chronic inflammation, usually without atrophy; (2) diffuse GC, which may be located anywhere in the stomach with no apparent gastritis that exhibits an entirely diffuse pattern of infiltration of cells with a poorly differentiated phenotype; and (3) distal nondiffuse GC, which is located mainly in the distal stomach with evidence of chronic gastritis that is predominantly differentiated or exhibits an intestinal phenotype In this study, they demonstrated that the three GC subtypes are distinguished by their gene expression profiles. The genetic diversity of GC subtypes should be considered in studies of genetic and epigenetic alterations related to gastric carcinogenesis and progression
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