Potential utility of HOP homeobox gene promoter methylation as a marker of tumor aggressiveness in gastric cancer

Abstract

HOP homeobox (HOPX) is an unusual homeobox gene encoding three spliced transcript variants, among which the only HOPX-b promoter harbors CpG islands. The characteristics of its promoter methylation was analyzed using bisulfite sequencing and quantitative-methylationspecific polymerase chain reaction (Q-MSP), and the effects of HOPX expression were also examined. HOPX-b expression was silenced in all gastric cancer cell lines tested; its expression could be restored by treatment with demethylating agent. On Q-MSP, HOPX-b hypermethylation (cut-off value of 3.55) was found in 84% (67 out of 80) of primary tumor tissues and 10% (8 out of 80) of the corresponding normal tissues and could discriminate normal from tumor tissues (Po0.0001). The prognosis of the advanced cases with HOPX-b hypermethylation was as poor as those with stage IV disease when cut-off value was set at 11.28. This finding was validated in an independent cohort of 90 advanced gastric cancers. The HOPX-b hypermethylation was also an independent prognostic factor (P ¼ 0.029) on multivariate analysis. Exogenous HOPX expression significantly inhibited cell proliferation, colony formation and invasion as well as enhanced apoptosis. Taken together, HOPX-b promoter methylation is a frequent and cancer-specific event in gastric cancer. Quantitative assessment of HOPX-b methylation has great clinical potential as a marker of tumor aggressiveness.

Comparison of genome-wide and gene-specific DNA methylation between ART and naturally conceived pregnancies

“…One of this genes is HOP which encodes the Hsp70-Hsp90 Organizing Protein (gene ID 84525), and abnormal methylation of this gene has been recently associated with different types of cancer. [25][26][27] The differential methylation of HOP in the ART group was confirmed using a pyrosequencing assay (Fig. 5).…”

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

“…Previous work documented the decreased HOPX expression in several types of human cancer. Explicitly, HOPX was suggested as tumor suppressor in esophageal and gastric cancer (17,23). These studies, however, did not study the role of HOPX in tumor dissemination and metastasis.…”

“…1A) and found a significant decrease in the HOPX mRNA level in PR9692-E9 cells. Transcriptional suppression of HOPX expression has repeatedly been correlated with promoter hypermethylation (15,16,23,24). To test the epigenetic character of HOPX suppression, we examined the HOPX methylation status in PR9692 and PR9692-E9 cells by bisulfite sequencing.…”

DNA Damage-Inducible Gene, Reprimo Functions as a Tumor Suppressor and Is Suppressed by Promoter Methylation in Gastric Cancer

“…1A. The Reprimo promoter harbors CpG islands encompassing the transcription start site, and we previously reported that Reprimo harbored its promoter methylation in 75% (6/8) of gastric cancer cell lines, 80% (8/10) of primary human gastric cancer tissues, and 10% (1/10) of corresponding normal tissues in the preliminary dataset of 10 matched pairs by bisulfite sequencing analysis (15). Q-MSP can achieve a much more objective and specific assessment of a small amount of genomic DNA through PCR amplification using methylation-specific primers and fluorescent probes (22).…”

“…Furthermore, the regulation of Reprimo expression is independent of p53 status in neuronal cells treated with copper, with neuronal damage being associated with Wilson disease (14). In gastric cancer, Reprimo promoter methylation is a frequent event as we and others have previously reported (11,13,15). The relationship between Reprimo and gastric cancer, however, has never been examined from a mechanistic and functional point of view.…”