Pyridoxine 5′-phosphate oxidase is a novel therapeutic target and regulated by the TGF-β signalling pathway in epithelial ovarian cancer

Abstract

Pyridoxine 5′-phosphate oxidase (PNPO) is an enzyme that converts pyridoxine 5′-phosphate into pyridoxal 5′-phosphate (PLP), an active form of vitamin B6 implicated in several types of cancer. However, the role of PNPO and its regulatory mechanism in epithelial ovarian cancer (EOC) are unknown. In the present study, PNPO expression in human ovarian tumour tissue and its association with the clinicopathological features of patients with EOC were examined. Further, the biological function of PNPO in EOC cells and in xenograft was evaluated. We demonstrated for the first time that PNPO was overexpressed in human EOC. Knockdown of PNPO induced EOC cell apoptosis, arrested cell cycle at G2/M phase, decreased cell proliferation, migration and invasion. Xenografts of PNPO-shRNA-expressing cells into the nude mouse attenuated tumour growth. PNPO at mRNA and protein levels in EOC cells was decreased after transforming growth factor-β1 (TGF-β1) treatment. The inhibitory effect of TGF-β1 on PNPO expression was abolished in the presence of SB-431542, a TGF-β type I receptor kinase inhibitor. Moreover, we found that TGF-β1-mediated PNPO expression was at least in part through the upregulation of miR-143-3p. These data indicate a mechanism underlying PNPO regulation by the TGF-β signalling pathway. Furthermore, PLP administration reduced PNPO expression and decreased EOC cell proliferation, suggesting a feedback loop between PLP and PNPO. Thus, our findings reveal that PNPO can serve as a novel tissue biomarker of EOC and may be a potential target for therapeutic intervention.

An integrative multi-omics network-based approach identifies key regulators for breast cancer

“…CDK6 and MLLT10 have been identified as cancer driver genes according to the COSMIC database. By manually checking in the PubMed, 7 of the top 20 genes were reported to be relevant to ovarian cancer, including MAPT [55] , BECN1 [56] , PRC1 [57] , CBX1 [58] , CDK6 [59] , WWOX [60] , and PNPO [61] . We performed KEGG pathway enrichment analysis for the top 100 genes ( Figure Supplementary Fig.…”

Integrating germline and somatic genetics to identify genes associated with lung cancer

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“…In TWAS, weights w w (ˆ, …,ˆ) k 1 are estimated using a prediction method, such as a Bayesian linear mixed model (Zhou, Carbonetto, & Stephens, 2013) or an elastic net (Zou & Hastie, 2005). In our analysis, we use the elastic net.…”

Benign and severe early-life seizures: a round in the first year of life

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