Aberrant SOX11 promoter methylation is associated with poor prognosis in gastric cancer

Abstract

Background: Gastric cancer (GC) is the second most common cause of cancer mortality world-wide. In recent years, aberrant SOX11 expression has been observed in various solid and hematopoietic malignancies, including GC. In addition, it has been reported that SOX11 expression may serve as an independent prognostic factor for the survival of GC patients. Here, we assessed the SOX11 gene promoter methylation status in various GC cell lines and primary GC tissues, and evaluated its clinical significance.

Methods: Five GC cell lines were used to assess SOX11 expression by qRT-PCR. The effect of SOX11 expression restoration after 5-aza-2'-deoxycytidine (5-Aza-dC) treatment on GC growth was evaluated in GC cell line MKN45. Subsequently, 89 paired GC-normal gastric tissues were evaluated for their SOX11 gene promoter methylation status using methylation-specific PCR (MSP), and 20 paired GC-normal gastric tissues were evaluated for their SOX11 expression in relation to SOX11 gene promoter methylation. GC patient survival was assessed by Kaplan-Meier analyses and a Cox proportional hazard model was employed for multivariate analyses.

Results: Down-regulation of SOX11 mRNA expression was observed in both GC cell lines and primary GC tissues. MSP revealed hyper-methylation of the SOX11 gene promoter in 55.1% (49/89) of the primary GC tissues tested and in 7.9% (7/89) of its corresponding non-malignant tissues. The SOX11 gene promoter methylation status was found to be related to the depth of GC tumor invasion, Borrmann classification and GC differentiation status. Upon 5-Aza-dC treatment, SOX11 expression was found to be up-regulated in MKN45 cells, in conjunction with proliferation inhibition. SOX11 gene promoter hyper-methylation was found to be significantly associated with a poor prognosis and to serve as an independent marker for survival using multivariate Cox regression analysis.

Conclusions: Our results indicate that aberrant SOX11 gene promoter methylation may underlie its down-regulation in GC. SOX11 gene promoter hyper-methylation may serve as a biomarker to predict the clinical outcome of GC.