HOXA11 gene is hypermethylation and aberrant expression in gastric cancer

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.

HOXA9 is Underexpressed in Cervical Cancer Cells and its Restoration Decreases Proliferation, Migration and Expression of Epithelial-to-Mesenchymal Transition Genes

“…The expression of HOXA11 was found unchanged in normal and malignant cervical cells (Lopez et al, 2006b). A report from Bai et al indicates that HOXA11 is regulated by methylation and that the expression of this gene decreases in gastric cancer; moreover, these authors observed that silencing of HOXA11 induced cell proliferation of tumor cells (Bai et al, 2014).…”

The function of homeobox genes and lncRNAs in cancer

“…A study by Bai et al (64) observed that the methylation frequencies of HOXA11 in gastric cancer tissues and adjacent cancer tissues were higher than those in normal gastric mucosa (P<0.05). Furthermore, HOXA11 expression was downregulated following hypermethylation of the promoter region (64); this suggests that HOXA11 may function as an important repressor in gastric cancer tumorigenesis, and aberrant promoter methylation may be the primary cause behind the loss or downregulation of HOXA11 expression, subsequently resulting in gastric cancer carcinogenesis.…”

“…A study by Bai et al (64) observed that the methylation frequencies of HOXA11 in gastric cancer tissues and adjacent cancer tissues were higher than those in normal gastric mucosa (P<0.05). Furthermore, HOXA11 expression was downregulated following hypermethylation of the promoter region (64); this suggests that HOXA11 may function as an important repressor in gastric cancer tumorigenesis, and aberrant promoter methylation may be the primary cause behind the loss or downregulation of HOXA11 expression, subsequently resulting in gastric cancer carcinogenesis. The study also observed that hypermethylation of HOXA11 was significantly associated with lymph node metastasis and Tumor-Node-Metastasis stage in gastric cancer, and in vitro experiments demonstrated that HOXA11 may control cell growth with its defect enhancing cell proliferation (64).…”

“…It was identified that different expression levels of HOXC11 represented different functions, with overexpression promoting proliferation and downregulation inhibiting proliferation (64). In addition, the study reported that high immunohistochemical expression of HOXC11 was associated with T stage, N stage and Ki67 level in RCC (65).…”

Long non-coding RNA HOXA transcript at the distal tip as a biomarker for gastric cancer

“…It was reported that HOTTIP may regulate the expression of HOX genes, including HOXA1, HOXA9, HOXA10, HOXA11 and HOXA13, in liver cancer and pancreatic cancer (15)(16)(17). In addition, numerous studies have reported that aberrant expression of HOXA genes was associated with a number of biological characteristics of gastric cancer (34)(35)(36)(37). HOTTIP may be critical in regulating HOXA genes in gastric cancer, but the underlying mechanism remains unknown and requires additional study.…”