Abstract
Inorganic pyrophosphatase (PPA1) activity is a key determinant of cellular inorganic pyrophosphate levels, and its expression is correlated with growth of several solid tumors. To investigate this relationship, we first examined PPA1 expression in human epithelial ovarian cancer (EOC) samples, and found that PPA1 was overexpressed in tumors from EOC patients. Higher PPA1 levels correlated with advanced grades, stages, and poor survival in EOC patients. Examination of PPA1 function in EOC revealed that silencing PPA1 inhibited EOC migration, epithelial-mesenchymal transition (EMT), and metastasis in vitro and in vivo. In addition, PPA1 may promote the dephosphorylation and translocation of β-catenin. These results demonstrate that silencing PPA1 inhibits EOC metastasis by suppressing the Wnt/β-catenin signaling pathway. Strategies for downregulating PPA1 may have therapeutic potential for the prevention and treatment of EOC.
Highlights
Epithelial ovarian cancer (EOC) accounts for more than 90% of ovarian cancers
To explore the clinical significance of PPA1 in epithelial ovarian cancer (EOC), the expression of PPA1 was detected in frozen primary EOC samples (n=26) and normal ovarian tissues (n=8) using Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis (Figure 1A)
PPA1 expression was upregulated in EOC tissues compared to PPA1 expression in normal ovarian tissues (p
Summary
Epithelial ovarian cancer (EOC) accounts for more than 90% of ovarian cancers. Despite continued efforts to improve EOC treatment, it is still the fifth leading cause of cancer death among women [1]. Metastasis is a multistep process that includes epithelial–mesenchymal transition (EMT) of tumor cells, collective invasion, reorganization of cytoskeleton, and microenvironment remodeling [2, 3]. Better understanding of the molecular mechanisms involved in EMT is important for identifying novel therapeutic targets and establishing new treatment strategies for EOC. Inorganic pyrophosphatase (PPA1) has been identified as a soluble cytosolic pyrophosphatase, which was found to be essential for growth and development in the round-worms Ascaris and Caenorhabditis elegans [4, 5]. PPA1 has the potential to regulate neurite growth via JNK dephosphorylation in mouse neuroblastoma cells [6], as well as the potential to induce type I collagen synthesis and stimulate calcification by osteoblasts [7]. Increases in the expression and activity of PPA1 in rat and mouse livers are correlated with aging [8, 9]
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