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Silencing PPA1 inhibits human epithelial ovarian cancer metastasis by suppressing the Wnt/?-catenin signaling pathway.

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 ?-catenin. These results demonstrate that silencing PPA1 inhibits EOC metastasis by suppressing the Wnt/?-catenin signaling pathway. Strategies for downregulating PPA1 may have therapeutic potential for the prevention and treatment of EOC.

SUBMITTER: Niu H

PROVIDER: S-EPMC5652704 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Silencing PPA1 inhibits human epithelial ovarian cancer metastasis by suppressing the Wnt/β-catenin signaling pathway.

Niu Haiying H Zhou Wei W Xu Yingxi Y Yin Zhiqi Z Shen Wenzhi W Ye Zhen Z Liu Yanhua Y Chen Yanan Y Yang Shuang S Xiang Rong R Wang Lina L Qu Pengpeng P

Oncotarget 20170718 44

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 reveale ...[more]

PMID: 29100310

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Project description:Hepatocellular carcinoma (HCC) is one of the most lethal malignancies with extremely poor prognosis. Therefore, revealing the critical molecules involved in HCC progression and prognosis is urgently needed. In this study, through combining public dataset and our cohort, we found a novel prognosis-related long non-coding RNA KB-68A7.1 in HCC. KB-68A7.1 was lowly expressed in HCC, whose low expression was associated with large tumour size, aggressive clinical characteristic, and poor survival. Gain- and loss-of-function assays demonstrated that KB-68A7.1 restricted HCC cellular proliferation, induced HCC cellular apoptosis, and suppressed HCC cellular migration and invasion in vitro. Xenograft assays demonstrated that KB-68A7.1 suppressed HCC tumour growth and metastasis in vivo. These functional assays suggested KB-68A7.1 as a tumour suppressor in HCC. Histone methyltransferase nuclear receptor binding SET domain-containing protein 1 (NSD1) was found to bind to KB-68A7.1. KB-68A7.1 was mainly distributed in the cytoplasm. The binding of KB-68A7.1 to NSD1 sequestrated NSD1 in the cytoplasm, leading to the reduction in nuclear NSD1 level. Through decreasing nuclear NSD1 level, KB-68A7.1 reduced di-methylation of histone H3 at lysine 36 (H3K36me2) and increased tri-methylation of histone H3 at lysine 27 (H3K27me3) at the promoter of WNT10B, a target of NSD1. Thus, KB-68A7.1 repressed WNT10B transcription. The expression of WNT10B was negatively correlated with that of KB-68A7.1 in HCC tissues. Through repressing WNT10B, KB-68A7.1 further repressed Wnt/β-catenin signalling. Functional rescue assays showed that overexpression of WNT10B reversed the tumour-suppressive roles of KB-68A7.1, whereas the oncogenic roles of KB-68A7.1 depletion were abolished by Wnt/β-catenin signalling inhibitor. Overall, this study identified KB-68A7.1 as a lowly expressed and prognosis-related lncRNA in HCC, which suppressed HCC progression through binding to NSD1 and repressing Wnt/β-catenin signalling.

Dataset Information

Silencing PPA1 inhibits human epithelial ovarian cancer metastasis by suppressing the Wnt/?-catenin signaling pathway.

Publications

Silencing PPA1 inhibits human epithelial ovarian cancer metastasis by suppressing the Wnt/β-catenin signaling pathway.

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