Abstract
BackgroundAberrant DNA methylation is an acquired epigenetic alteration that serves as an alternative to genetic defects in the inactivation of tumor suppressor genes and other genes in diverse human cancers. Gastric carcinoma is one of the tumors with a high frequency of aberrant methylation in promoter region. Hence we investigated the promoter methylation status and expression level of HOXA11 gene which may involve in GC development.MethodsThirty-two surgical excised gastric cancer specimens, twelve paired adjacent non-cancerous specimens and seven normal gastric mucosas were examined. The methylation status and expression level of HOXA11 gene were determined by bisulfite sequencing polymerase chain reaction (BSP), real-time polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) respectively. HOXA11 expression was knocked-down with siRNA to mimic HOXA11 gene hypermethylation and ability of cell proliferation and migration was determinate. In addition, we analyzed and correlated the findings with clinicopathological features.ResultsThe methylation level of HOXA11 gene in gastric cancer tissues and adjacent non-cancerous tissues were higher than those in normal gastric mucosa (P < 0.05). The methylation level was higher in TNM III and IV patients of GC than those in TNM I and II patients (P < 0.05). The expression of HOXA11 mRNA and protein decreased in normal gastric mucosa, peri-cancer tissue and GC (P < 0.05). HOXA11 expression was inversely correlated with DNA methylation (P < 0.05). Knocked-down of HOXA11 expression with siRNA in BGC-823 cells enhanced cell proliferation compared with control, but no significant different was observed in migration ability.ConclusionHypermethylation and decreased expression of HOXA11 gene may be involved in the carcinogenesis and development of GC and may provide useful information for the prediction of the malignant behaviors of GC. And the expression of HOXA11 is impaired by DNA methylation. However, repression of HOXA11 expression promoted BGC-823 cell proliferation.
Highlights
Aberrant DNA methylation is an acquired epigenetic alteration that serves as an alternative to genetic defects in the inactivation of tumor suppressor genes and other genes in diverse human cancers
The methylation frequencies of HOXA11 in cancer tissues, peri-cancer tissue specimens were higher than those in normal gastric mucosa (P = 0.007, P = 0.035), but no difference was seen between the adjacent non-cancerous specimens and normal gastric mucosa (P < 0.05)
Clinico-pathological correlations with methylation profile The methylation level of HOXA11 gene was higher in TNM III and IV patients of Gastric cancer (GC) than that in TNM I and IIpatients (P < 0.05, Table 1)
Summary
Aberrant DNA methylation is an acquired epigenetic alteration that serves as an alternative to genetic defects in the inactivation of tumor suppressor genes and other genes in diverse human cancers. Gastric carcinoma is one of the tumors with a high frequency of aberrant methylation in promoter region. We investigated the promoter methylation status and expression level of HOXA11 gene which may involve in GC development. The HOXA cluster, located within a 155kb-long genomic region on chromosome 7p15-7p14.2 consists of 12 genes (11 HOX genes and EVX1). Dense CpG islands are prevalent in most of the HOXA promoters and the hypermethylation of these islands plays pivotal roles in the control of HOXA gene expression. Among HOXA genes, HOXA11 hypermethylation has recently been reported in endometrial carcinoma, ovarian cancer, glioblastoma multiforme and cervical cancer [9,10,11,12]. Relationship between HOXA11 hypermethylation and tumor development currently becomes an active exploring area in recent years
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