Abstract
In several types of human cancer, the gene expression of Reprimo, a highly glycosylated protein, is frequently silenced via methylation of its promoter. The aim of this study was to characterize the epigenetic inactivation of Reprimo and its biologic function and clinical relevance in gastric cancer. The correlation between Reprimo methylation and clinical relevance was assessed in 83 primary human gastric cancer tissues. The effects of Reprimo expression were also examined using in vitro and in vivo assays. Reprimo methylation was cancer specific and frequently observed. In two gastric cancer cell lines without Reprimo methylation, we observed faint or weak Reprimo expression under normal conditions and high expression under DNA-damaging conditions. In four gastric cancer cell lines with Reprimo methylation, however, Reprimo expression remained faint even under DNA-damaging conditions, with expression being restored in combination with agents that induce demethylation. Enforced Reprimo expression robustly inhibited cell proliferation and anchorage-independent colony formation and enhanced DNA damage-induced apoptosis. Inverse effects were observed via siRNA-mediated knockdown of endogenous Reprimo. Reprimo expression inhibited tumorigenesis in vivo. Reprimo methylation was also associated with a poor response in patients with gastric cancer treated with chemotherapy (P¼ 0.028), and a poor prognosis in patients with advanced gastric cancer (P¼ 0.03). In conclusion, Reprimo expression is normally induced in response to DNA damage, acting as a novel tumor suppressor in gastric cancer. However, Reprimo methylation abrogates its expression and effects. The clinical assessment of Reprimo promoter methylation may serve not only as a predictive marker for chemotherapy, but also as a marker for tumor aggressiveness.
Highlights
Gastric cancer remains a major clinical challenge, being both the fourth most common cancer and the second leading cause of cancer-related death worldwide [1]
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]
We previously reported that Reprimo promoter methylation was one of the most frequent cancer-specific alterations, using bisulfite sequencing analysis in primary gastric cancer tissues [15]
Summary
Gastric cancer remains a major clinical challenge, being both the fourth most common cancer and the second leading cause of cancer-related death worldwide [1]. The epigenetic pathway involved in the development of cancer is determined by chromatin structure, including DNA methylation, histone modifications, or noncoding regulatory RNAs [4]. When methylation occurs within dinucleiotide CpG-rich regions, "CpG islands," of a gene promoter, it is associated with a compact chromatin structure and is accompanied by transcriptional silencing of the affiliated gene, especially tumor-suppressor genes [5]. DNA methylation occurs more frequently than genetic mutations in gastric cancer and has recently opened the exciting doors for developing cancer biomarkers and therapeutic targets [6,7,8]
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