Phosphoinositide-Dependent Signaling in Cancer: A Focus on Phospholipase C Isozymes

Obeng, Eric Owusu; Rusciano, Isabella; Marvi, Maria Vittoria; Fazio, Alessia; Ratti, Stefano; Follo, Matilde Y.; Xian, Jie; Manzoli, Lucia; Billi, Anna Maria; Mongiorgi, Sara; Ramazzotti, Giulia; Cocco, Lucio

doi:10.3390/ijms21072581

Cited by 55 publications

(34 citation statements)

References 113 publications

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“…In terms of molecular functions, the accumulation of errors during DNA transcription under the action of RNA polymerase is the source of genomic instability in all organisms ( Khristich and Mirkin, 2020 ). Additionally, phospholipase C participates in numerous physiological processes within the cell, especially signal transduction pathways that regulate cell functions and proliferation ( Jang et al, 2018 ; Owusu Obeng et al, 2020 ). These processes are also involved with genomic mutations and even lead to cancers ( Koss et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Prognostic Immunity and Therapeutic Sensitivity Analyses Based on Differential Genomic Instability-Associated LncRNAs in Left- and Right-Sided Colon Adenocarcinoma

Guo

Xia

Deng

et al. 2021

Front. Mol. Biosci.

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Background: The purpose of our study was to develop a prognostic risk model based on differential genomic instability-associated (DGIA) long non-coding RNAs (lncRNAs) of left-sided and right-sided colon cancers (LCCs and RCCs); therefore, the prognostic key lncRNAs could be identified.Methods: We adopted two independent gene datasets, corresponding somatic mutation and clinical information from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Identification of differential DGIA lncRNAs from LCCs and RCCs was conducted with the appliance of “Limma” analysis. Then, we screened out key lncRNAs based on univariate and multivariate Cox proportional hazard regression analysis. Meanwhile, DGIA lncRNAs related prognostic model (DRPM) was established. We employed the DRPM in the model group and internal verification group from TCGA for the purpose of risk grouping and accuracy verification of DRPM. We also verified the accuracy of key lncRNAs with GEO data. Finally, the differences of immune infiltration, functional pathways, and therapeutic sensitivities were analyzed within different risk groups.Results: A total of 123 DGIA lncRNAs were screened out by differential expression analysis. We obtained six DGIA lncRNAs by the construction of DRPM, including AC004009.1, AP003555.2, BOLA3-AS1, NKILA, LINC00543, and UCA1. After the risk grouping by these DGIA lncRNAs, we found the prognosis of the high-risk group (HRG) was significantly worse than that in the low-risk group (LRG) (all p < 0.05). In all TCGA samples and model group, the expression of CD8+ T cells in HRG was lower than that in LRG (all p < 0.05). The functional analysis indicated that there was significant upregulation with regard to pathways related to both genetic instability and immunity in LRG, including cytosolic DNA sensing pathway, response to double-strand RNA, RIG-Ⅰ like receptor signaling pathway, and Toll-like receptor signaling pathway. Finally, we analyzed the difference and significance of key DGIA lncRNAs and risk groups in multiple therapeutic sensitivities.Conclusion: Through the analysis of the DGIA lncRNAs between LCCs and RCCs, we identified six key DGIA lncRNAs. They can not only predict the prognostic risk of patients but also serve as biomarkers for evaluating the differences of genetic instability, immune infiltration, and therapeutic sensitivity.

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Section: Discussionmentioning

confidence: 99%

Prognostic Immunity and Therapeutic Sensitivity Analyses Based on Differential Genomic Instability-Associated LncRNAs in Left- and Right-Sided Colon Adenocarcinoma

Guo

Xia

Deng

et al. 2021

Front. Mol. Biosci.

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“…In addition, bile acid can also be used as an inflammatory stimulator to stimulate the production of many inflammatory mediators, thus promoting the inflammatory response of the liver. Studies have shown that linoleic acid metabolism and phosphatidylinositol-related metabolism are involved in a variety of inflammatory signal transduction (Owusu Obeng et al, 2020;Wang et al, 2021). The result showed that PF played a protective role in cholestatic liver injury by regulating inflammation-related pathways.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Paeoniflorin on ANIT-Induced Cholestatic Liver Injury Using Integrated Metabolomics and Network Pharmacology

et al. 2021

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Background: Paeoniflorin (PF), the major active compound isolated from the roots of Paeonia lactiflora Pall., has been used in the treatment of severe hepatic diseases for several decades and displays bright prospects in liver protective effect. However, its biological mechanism that regulates bile acid metabolism and cholestatic liver injury has not been fully elucidated. Our study aims to investigate the mechanism by which PF in the treatment of cholestatic liver injury using a comprehensive approach combining metabolomics and network pharmacological analysis.Methods: The hepatoprotective effect of PF against cholestasis liver injury, induced by α-naphthylisothiocyanate (ANIT), was evaluated in rats. The serum biochemical indices including ALT, AST, TBA, TBIL, ALP, ALB, and the pathological characteristics of the liver were analyzed. Moreover, UHPLC-Q-TOF was performed to explore the feces of rats with ANIT-induced cholestatic liver injury treated with PF and the potential biomarkers were screened by metabolomics. The targets for the regulation of potential biomarkers by PF were screened by network pharmacology, and then the relevant key targets were verified by immunohistochemical and western blotting methods.Results: PF significantly improved serum indexes and alleviated liver histological damage. Metabolomics analyses showed that the therapeutic effect of PF is mainly associated with the regulation of 13 metabolites involved in 16 metabolic pathways. The “PF-targets-metabolites” interaction network was constructed, and then five key targets including CDC25B, CYP2C9, MAOB, mTOR, and ABCB1 that regulated the potential biomarkers were obtained. The above five targets were further verified by immunohistochemistry and western blotting, and the results showed that PF significantly improved the expression of key proteins regulating these biomarkers.Conclusion: Our study provides direct evidence for the modulatory properties of PF treatment on ANIT-induced cholestatic liver injury using metabolomics and network pharmacology analyses. PF exhibits favorable pharmacological effect by regulating related signal pathways and key targets for biomarkers. Therefore, these findings may help better understand the complex mechanisms and provide a new and effective approach to the treatment of cholestatic liver injury.

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“…Phosphoinositides (PIs) form just a minor portion of the total phospholipid content in cells, but they are significantly involved in cancer development and progression [ 51 ]. PI metabolism includes phospholipases, a family of phospholipid metabolizing enzymes that catalyze the production of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) as secondary messengers implicated in several downstream pathways [ 52 ]. Four major families of phospholipases have been identified so far: A, B, C and D. Among all the phospholipases C (PLCs), nuclear PLCβ1 is an essential enzyme that regulates cell proliferation and differentiation in several systems [ 53 ].…”

Section: Targeting Inositide-dependent Signal Transduction Pathwaymentioning

confidence: 99%

Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia

Parisi

Finelli

Fazio

et al. 2021

IJMS

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Erythropoiesis regulation is essential in normal physiology and pathology, particularly in myelodysplastic syndromes (MDS) and β-thalassemia. Several signaling transduction processes, including those regulated by inositides, are implicated in erythropoiesis, and the latest MDS or β-thalassemia preclinical and clinical studies are now based on their regulation. Among others, the main pathways involved are those regulated by transforming growth factor (TGF)-β, which negatively regulates erythrocyte differentiation and maturation, and erythropoietin (EPO), which acts on the early-stage erythropoiesis. Also small mother against decapentaplegic (SMAD) signaling molecules play a role in pathology, and activin receptor ligand traps are being investigated for future clinical applications. Even inositide-dependent signaling, which is important in the regulation of cell proliferation and differentiation, is specifically associated with erythropoiesis, with phospholipase C (PLC) and phosphatidylinositol 3-kinase (PI3K) as key players that are becoming increasingly important as new promising therapeutic targets. Additionally, Roxadustat, a new erythropoiesis stimulating agent targeting hypoxia inducible factor (HIF), is under clinical development. Here, we review the role and function of the above-mentioned signaling pathways, and we describe the state of the art and new perspectives of erythropoiesis regulation in MDS and β-thalassemia.

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Phosphoinositide-Dependent Signaling in Cancer: A Focus on Phospholipase C Isozymes

Cited by 55 publications

References 113 publications

Prognostic Immunity and Therapeutic Sensitivity Analyses Based on Differential Genomic Instability-Associated LncRNAs in Left- and Right-Sided Colon Adenocarcinoma

Prognostic Immunity and Therapeutic Sensitivity Analyses Based on Differential Genomic Instability-Associated LncRNAs in Left- and Right-Sided Colon Adenocarcinoma

Mechanism of Paeoniflorin on ANIT-Induced Cholestatic Liver Injury Using Integrated Metabolomics and Network Pharmacology

Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia

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