Abstract
Background: We have recently reported the downregulation of the Metallophosphoesterase-domain-containing protein 2 (MPPED2) gene and its cognate long non-coding RNA, MPPED2-AS1, 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. Methods: In order to verify MPPED2 expression, 45 human breast carcinoma samples have been investigated by quantitative real-time polymerase chain reaction (qRT-PCR). Then, MPPED2 has been transfected in several human breast carcinoma cell lines, analyzing its role in cell proliferation, migration and invasion. To study the regulation of MPPED2 expression the methylation of its promoter was investigated by targeted bisulfite sequencing. Results: MPPED2 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 MPPED2 promoter likely accounted for its downregulation in breast cancer. Additionally, MPPED2-AS1 was also found downregulated in breast cancer tissues and, intriguingly, its expression decreased the hypermethylation of the MPPED2 promoter by inhibiting DNA methyltransferase 1 (DNMT1). Furthermore, the restoration of MPPED2 expression reduced cell proliferation, migration and invasion capability of breast carcinoma cell lines. Conclusion: Taken together, these results propose MPPED2 downregulation as a critical event in breast carcinogenesis.
Highlights
The Metallophosphoesterase-domain-containing protein 2 (MPPED2) belongs to the Class III of cyclic nucleotide phosphodiesterases (PDEs) and represents the first evidence of Class III-PDE identified in mammals [1]
We evaluated Metallophosphoesterasedomain-containing protein 2 (MPPED2) mRNA levels in a panel of 45 human breast cancer (BC) tissues by quantitative real-time polymerase chain reaction
MPPED2 expression levels were analyzed in the different BC molecular subtypes of the The Cancer Genome Atlas (TCGA) cohort (Lum A, luminal B (Lum B), human epidermal growth factor receptor 2 (HER2) and triple-negative breast cancer (TNBC)): as reported in Figure 1C, MPPED2 was found to be downregulated in all molecular subtypes (****, p < 0.0001), in particular in HER2 and in TNBC ones
Summary
The Metallophosphoesterase-domain-containing protein 2 (MPPED2) belongs to the Class III of cyclic nucleotide phosphodiesterases (PDEs) and represents the first evidence of Class III-PDE identified in mammals [1]. It has been reported that MPPED2 protein exhibits low phosphodiesteric activity against cyclic adenosine 30 ,50 -monophosphate (cAMP) and cyclic guanosine 30 ,50 -monophosphate (cGMP), due to an aminoacidic replacement in the highly conserved catalytic site at position 252, where a glycine residue replaces a histydine [3]. This unique substitution allows the active site of MPPED2 to retain AMP or GMP with strong affinity, leading the protein to have low catalytic efficiency [4]. We decided to investigate their role in breast carcinogenesis
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