Novel genomic targets of valosin-containing protein in protecting pathological cardiac hypertrophy

Zhou, Ning; Chen, Xin; Xi, Jing; Ma, Ben; Leimena, Christiana; Stoll, Shaunrick; Qin, Gangjian; Wang, Charles; Qiu, Hongyu

doi:10.1038/s41598-020-75128-z

Cited by 10 publications

(11 citation statements)

References 47 publications

(65 reference statements)

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“…SORBS1 encodes a CasitasB.1ineagelymphoma (CBL)–associated protein that functions in the signaling and stimulation of insulin, and it also been confirmed to be related to COPD. 81–83 Studies have found that SORBS1 can participate in immune-related gene signal transduction, and its increased expression is closely related to poor prognosis in cervical cancer, 84 gastric cancer, 85 prostate cancer, 86 and colorectal cancer. 87 However, the exact role and diagnostic significance of SORBS1 in BRCA are not yet clear.…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of a Prognostic Classifier Based on Lipid Metabolism-Related Genes for Breast Cancer

Wang¹,

Gu²,

Li³

et al. 2022

JIR

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Background The changes of lipid metabolism have been implicated in the development of many tumors, but its role in breast invasive carcinoma (BRCA) remains to be fully established. Here, we attempted to ascertain the prognostic value of lipid metabolism-related genes in BRCA. Methods We obtained RNA expression data and clinical information for BRCA and normal samples from public databases and downloaded a lipid metabolism-related gene set. Ingenuity Pathway Analysis (IPA) was applied to identify the potential pathways and functions of Differentially Expressed Genes (DEGs) related to lipid metabolism. Subsequently, univariate and multivariate Cox regression analyses were utilized to construct the prognostic gene signature. Functional enrichment analysis of prognostic genes was achieved by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Kaplan-Meier analysis, Receiver Operating Characteristic (ROC) curves, clinical follow-up results were employed to assess the prognostic potency. Potential compounds targeting prognostic genes were screened by Connectivity Map (CMap) database and a prognostic gene-drug interaction network was constructed using Comparative Toxicogenomics Database (CTD). Furthermore, we separately validated the selected marker genes in BRCA samples and human breast cancer cell lines (MCF-7, MDA-MB-231). Results IPA and functional enrichment analysis demonstrated that the 162 lipid metabolism-related DEGs we obtained were involved in many lipid metabolism and BRCA pathological signatures. The prognostic classifier we constructed comprising SDC1 and SORBS1 can serve as an independent prognostic marker for BRCA. CMap filtered 37 potential compounds against prognostic genes, of which 16 compounds could target both two prognostic genes were identified by CTD. The functions of the two prognostic genes in breast cancer cells were verified by cell function experiments. Conclusion Within this study, we identified a novel prognostic classifier based on two lipid metabolism-related genes: SDC1 and SORBS1 . This result highlighted a new perspective on the metabolic exploration of BRCA.

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Section: Discussionmentioning

confidence: 99%

Development and Validation of a Prognostic Classifier Based on Lipid Metabolism-Related Genes for Breast Cancer

Wang¹,

Gu²,

Li³

et al. 2022

JIR

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“…Our previous studies demonstrated a strong link between the down-regulation of VCP expression and cardiomyocyte hypertrophy and heart failure under pressure-overload stress [ 15 , 18 ]. We also showed that overexpression of VCP protects the heart against cardiac injuries and prevents cardiac deterioration under various stress conditions [ 15 , 16 , 18 , 19 , 20 , 21 ]. These results indicate that VCP is a crucial protector in the stressed heart.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous studies have demonstrated that VCP was decreased in the hypertensive rat hearts and acts as a driving force for the cardiac pathogenesis caused by pressure overload [ 15 ]. Reciprocally, cardiac-specific overexpressing VCP protects mouse hearts against pressure-overload-induced pathological hypertrophy [ 15 , 16 , 17 ] and heart failure [ 18 ], and it also protects against stress-induced cardiomyocyte death in vitro and reduced ischemic injury in vivo [ 19 , 20 , 21 ]. These results together indicated that VCP plays a critical protective role in the heart under stress conditions.…”

Section: Introductionmentioning

confidence: 99%

Functional Inhibition of Valosin-Containing Protein Induces Cardiac Dilation and Dysfunction in a New Dominant-Negative Transgenic Mouse Model

Sun

Zhou

et al. 2021

Cells

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Valosin-containing protein (VCP) was found to play a vital protective role against cardiac stresses. Genetic mutations of VCP are associated with human dilated cardiomyopathy. However, the essential role of VCP in the heart during the physiological condition remains unknown since the VCP knockout in mice is embryonically lethal. We generated a cardiac-specific dominant-negative VCP transgenic (DN-VCP TG) mouse to determine the effects of impaired VCP activity on the heart. Using echocardiography, we showed that cardiac-specific overexpression of DN-VCP induced a remarkable cardiac dilation and progressively declined cardiac function during the aging transition. Mechanistically, DN-VCP did not affect the endogenous VCP (EN-VCP) expression but significantly reduced cardiac ATPase activity in the DN-VCP TG mouse hearts, indicating a functional inhibition. DN-VCP significantly impaired the aging-related cytoplasmic/nuclear shuffling of EN-VCP and its co-factors in the heart tissues and interrupted the balance of the VCP-cofactors interaction between the activating co-factors, ubiquitin fusion degradation protein 1 (UFD-1)/nuclear protein localization protein 4 (NPL-4) complex, and its inhibiting co-factor P47, leading to the binding preference with the inhibitory co-factor, resulting in functional repression of VCP. This DN-VCP TG mouse provides a unique functional-inactivation model for investigating VCP in the heart in physiological and pathological conditions.

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“…The genes we used for prognostic classifier constructing were SORBS1 and SDC1. SORBS1 encodes a CasitasB.1ineagelymphoma (CBL)-associated protein that functions in the signaling and stimulation of insulin, and it also been confirmed to be related to COPD [80][81][82] . Studies have found that SORBS1 can participate in immune-related gene signal transduction, and its increased expression is closely related to poor prognosis in cervical cancer 83 , gastric cancer 84 , prostate cancer 85 , and colorectal cancer 86 .…”

Section: Prognostic Gene-drug Interaction Network Analysismentioning

confidence: 99%

Development and Validation of a Prognostic Classifier Based on Metabolism-Related Genes for Breast Cancer

Wang

Chi

et al. 2021

Preprint

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Background: Alterations in lipid metabolism have been implicated in the development of many tumors. However, the contribution of different lipid metabolism pathways to Breast invasive carcinoma (BRCA) remains to be fully established. Here, we attempted to ascertain the prognostic value of lipid metabolism-related genes in BRCA. Methods: We obtained RNA expression data and clinical information for BRCA and normal samples from public databases and downloaded a lipid metabolism-related gene set to harvest lipid metabolism-related genes. IPA was applied to identify the potential pathways and functions of DEGs related to lipid metabolism. Subsequently, univariate and multivariate Cox regression analyses were utilized to construct the prognostic gene signature and independent prognostic analyses. Thereafter, the differential expression of the selected marker genes SDC1 and SORBS1 in clinical tissue samples was verified by qRT-PCR, western blotting, and immunohistochemical experiments. Functional enrichment analysis of prognostic genes was achieved by the GO and KEGG databases. Moreover, Kaplan-Meier analysis, ROC curves, clinical immunohistochemistry conditions and follow-up results were employed to assess the prognostic potency. Potential compounds targeting prognostic genes were then screened by CMap database and a prognostic gene-drug interaction network was constructed using Comparative Toxicogenomics Database.Results: IPA demonstrated that the 162 lipid metabolism-related DEGs we obtained were involved in a variety of lipid metabolism and BRCA pathological signatures. Subsequent functional enrichment analysis of candidate prognostic lipid metabolism DEGs also revealed a similar outcome. The prognostic classifier we constructed comprising SDC1 and SORBS1 has a strong prognostic potency that was verified by the clinical conditions and follow-up results, it also can serve as an independent prognostic marker for BRCA. CMap filtered 37 potential compounds against prognostic genes. CTD indicated that the two prognostic genes had 16 drugs in common. Conclusion: Within this study, we identified a novel prognostic classifier based on two lipid metabolism-related genes: SDC1 and SORBS1. This classifier had accurately predicted the prognosis of our follow-up BRCA patients and this result highlighted a new perspective on the metabolic exploration of BRCA. In addition, SDC1 and SORBS1 could serve as a possible new target for the synthesis of BRCA drugs.

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Novel genomic targets of valosin-containing protein in protecting pathological cardiac hypertrophy

Cited by 10 publications

References 47 publications

Development and Validation of a Prognostic Classifier Based on Lipid Metabolism-Related Genes for Breast Cancer

Development and Validation of a Prognostic Classifier Based on Lipid Metabolism-Related Genes for Breast Cancer

Functional Inhibition of Valosin-Containing Protein Induces Cardiac Dilation and Dysfunction in a New Dominant-Negative Transgenic Mouse Model

Development and Validation of a Prognostic Classifier Based on Metabolism-Related Genes for Breast Cancer

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