<scp>ALDH5A1</scp> acts as a tumour promoter and has a prognostic impact in papillary thyroid carcinoma

Deng, Xiaofang; Gan, Xiao‐Xiong; Feng, Jianhua; Cai, Wei; Wang, Xinquan; Shen, Liang; Luo, Hong-Tu; Chen, Zhe; Guo, Mingming; Cao, Jie; Shen, Fei; Xu, Bo

doi:10.1002/cbf.3584

Cited by 14 publications

(9 citation statements)

References 39 publications

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“…Results will be critical for future development of AAV vectors that require incorporating cell-specific promoters [105]. Limiting SSADH restoration to relevant cell populations is particularly important from a metabolic homeostasis standpoint, given that aberrant aldh5a1 gene activities have been linked to oncogenesis [106,107]. This novel aldh5a1 STOP/STOP mouse will be useful as a platform to develop other novel SSADH-targeted strategies.…”

Section: The Novel Ssadhd Mouse Model Aldh5a1 Stop/stopmentioning

confidence: 99%

Understanding the Molecular Mechanisms of Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): Towards the Development of SSADH-Targeted Medicine

Lee

McGinty

Pearl

et al. 2022

IJMS

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Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare genetic disorder caused by inefficient metabolic breakdown of the major inhibitory neurotransmitter, γ-aminobutyric acid (GABA). Pathologic brain accumulation of GABA and γ-hydroxybutyrate (GHB), a neuroactive by-product of GABA catabolism, leads to a multitude of molecular abnormalities beginning in early life, culminating in multifaceted clinical presentations including delayed psychomotor development, intellectual disability, hypotonia, and ataxia. Paradoxically, over half of patients with SSADHD also develop epilepsy and face a significant risk of sudden unexpected death in epilepsy (SUDEP). Here, we review some of the relevant molecular mechanisms through which impaired synaptic inhibition, astrocytic malfunctions and myelin defects might contribute to the complex SSADHD phenotype. We also discuss the gaps in knowledge that need to be addressed for the implementation of successful gene and enzyme replacement SSADHD therapies. We conclude with a description of a novel SSADHD mouse model that enables ‘on-demand’ SSADH restoration, allowing proof-of-concept studies to fine-tune SSADH restoration in preparation for eventual human trials.

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Section: The Novel Ssadhd Mouse Model Aldh5a1 Stop/stopmentioning

confidence: 99%

Understanding the Molecular Mechanisms of Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): Towards the Development of SSADH-Targeted Medicine

Lee

McGinty

Pearl

et al. 2022

IJMS

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“…Nevertheless, some of the hub genes in our miRNA–mRNA network were poorly studied and have not been reported in RF before. The expression changes of Slc1a1 , Myo5a , and Aldh5a1 were known to affect cancer cell proliferation migration, invasion, and metastasis and may be critical for carcinoma pathophysiology ( Tian et al, 2017 ; Ergün et al, 2019 ; Tomic et al, 2020 ; Deng et al, 2021 ). In addition, a previous study revealed the correlation between the loss of Aldh5a1 and the presence of epithelial–mesenchymal transition ( Hilvo et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analyses of the microRNA–messenger RNA–transcription factor regulatory network in mouse and human renal fibrosis

Deng

Huang

2022

Front. Genet.

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Objective: The aim of this study was to construct a microRNA (miRNA)–messenger RNA (mRNA)–transcription factor (TF) regulatory network and explore underlying molecular mechanisms, effective biomarkers, and drugs in renal fibrosis (RF).Methods: A total of six datasets were downloaded from Gene Expression Omnibus. “Limma” and “DESeq2” packages in R software and GEO2R were applied to identify the differentially expressed miRNAs and mRNAs (DEmiRNAs and DEmRNAs, respectively). The determination and verification of DEmiRNAs and DEmRNAs were performed through the integrated analysis of datasets from five mouse 7 days of unilateral ureteral obstruction datasets and one human chronic kidney disease dataset and the Human Protein Atlas (http://www.proteinatlas.org). Target mRNAs of DEmiRNAs and TFs were predicted by prediction databases and the iRegulon plugin in Cytoscape, respectively. A protein–protein interaction network was constructed using STRING, Cytoscape v3.9.1, and CytoNCA. Functional enrichment analysis was performed by DIANA-miRPath v3.0 and R package “clusterProfiler.” A miRNA–mRNA–TF network was established using Cytoscape. Receiver operating characteristic (ROC) curve analysis was used to examine the diagnostic value of the key hub genes. Finally, the Comparative Toxicogenomics Database and Drug-Gene Interaction database were applied to identify potential drugs.Results: Here, 4 DEmiRNAs and 11 hub genes were determined and confirmed in five mouse datasets, of which Bckdha and Vegfa were further verified in one human dataset and HPA, respectively. Moreover, Bckdha and Vegfa were also predicted by miR-125a-3p and miR-199a-5p, respectively, in humans as in mice. The sequences of miR-125a-3p and miR-199a-5p in mice were identical to those in humans. A total of 6 TFs were predicted to regulate Bckdha and Vegfa across mice and humans; then, a miRNA–mRNA–TF regulatory network was built. Subsequently, ROC curve analysis showed that the area under the curve value of Vegfa was 0.825 (p = 0.002). Finally, enalapril was identified to target Vegfa for RF therapy.Conclusion: Pax2, Pax5, Sp1, Sp2, Sp3, and Sp4 together with Bckdha-dependent miR-125a-3p/Vegfa-dependent miR-199a-5p formed a co-regulatory network enabling Bckdha/Vegfa to be tightly controlled in the underlying pathogenesis of RF across mice and humans. Vegfa could act as a potential novel diagnostic marker and might be targeted by enalapril for RF therapy.

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“…The genetic alteration of ALDH5A1 and ABAT causes inherited disorders of gamma-aminobutyric acid (GABA) metabolism and may develop Alzheimer's Disease and paranoid schizophrenia [40,71,72]. Moreover, previous studies show that the decreased expression of ALDH5A1 in patients with ovarian cancer or papillary thyroid carcinoma may lead to a poor prognosis [73,74]. The interaction of ABAT and ALDH5A1 in tumor treatments may have a synergistic effect.…”

Section: Discussionmentioning

confidence: 99%

The Oncogenic Role of γ-Aminobutyrate Aminotransferase in Human Tumor: A Pan-Cancer Analysis

Wang

et al. 2022

Preprint

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Emerging evidence supports the correlation between γ-aminobutyrate aminotransferase (ABAT) and tumors, but few research groups used pan-cancer analysis to verify it previously. Therefore, this study used the Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) to obtain information about the correlations between ABAT and tumor development, and to explore its potential effectiveness for genetic alterations in tumor prognosis. The reduced expression level of ABAT in a majority of tumors is significantly associated with the poor prognosis. The genetic alteration of ABAT seems linked to the favorable prognosis of Uterine Corpus Endometrial Carcinoma (UCEC). Immune infiltration analysis showed a significantly positive correlation between ABAT and cancer-associated fibroblasts in the majority of tumors, but a highly negative correlation with Kidney renal clear cell carcinoma (KIRC), Kidney Renal Papillary cell carcinoma (KIRP), and Prostate adenocarcinoma (PRAD). Enrichment analysis showed that cell junction organization, amino acids metabolism, and neuronal system-involved behaviors might affect the pathogenesis or etiology of cancer. This study is the first pan-cancer analysis that offers a detailed, comprehensive study of the process of the oncogenic roles of ABAT across different human tumors.

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ALDH5A1 acts as a tumour promoter and has a prognostic impact in papillary thyroid carcinoma

Cited by 14 publications

References 39 publications

Understanding the Molecular Mechanisms of Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): Towards the Development of SSADH-Targeted Medicine

Understanding the Molecular Mechanisms of Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): Towards the Development of SSADH-Targeted Medicine

Comprehensive analyses of the microRNA–messenger RNA–transcription factor regulatory network in mouse and human renal fibrosis

The Oncogenic Role of γ-Aminobutyrate Aminotransferase in Human Tumor: A Pan-Cancer Analysis

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