| Summary: | <i>Background</i>: We have recently reported the downregulation of the <i>Metallophosphoesterase-domain-containing protein 2 (MPPED2)</i> gene and its cognate long non-coding RNA, <i>MPPED2-AS1</i>, in papillary thyroid carcinomas. Functional studies supported a tumor suppressor role of both these genes in thyroid carcinogenesis. We then decided to investigate their role in breast carcinogenesis. <i>Methods</i>: In order to verify <i>MPPED2</i> expression, 45 human breast carcinoma samples have been investigated by quantitative real-time polymerase chain reaction (qRT-PCR). Then, <i>MPPED2</i> has been transfected in several human breast carcinoma cell lines, analyzing its role in cell proliferation, migration and invasion. To study the regulation of <i>MPPED2</i> expression the methylation of its promoter was investigated by targeted bisulfite sequencing. <i>Results</i>: <i>MPPED2</i> expression was decreased in breast cancer samples, and this was confirmed by the analysis of data available in The Cancer Genome Atlas (TCGA). Interestingly, the hypermethylation of <i>MPPED2</i> promoter likely accounted for its downregulation in breast cancer. Additionally, <i>MPPED2-AS1</i> was also found downregulated in breast cancer tissues and, intriguingly, its expression decreased the hypermethylation of the <i>MPPED2</i> promoter by inhibiting DNA methyltransferase 1 (DNMT1). Furthermore, the restoration of <i>MPPED2</i> expression reduced cell proliferation, migration and invasion capability of breast carcinoma cell lines. <i>Conclusion</i>: Taken together, these results propose <i>MPPED2</i> downregulation as a critical event in breast carcinogenesis.
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