MOXD1 knockdown suppresses the proliferation and tumor growth of glioblastoma cells via ER stress-inducing apoptosis

Shi, Pengfei; Xu, Jie; Xia, Fanwei; Wang, Yinggang; Ren, Jie; Liang, Ping; Cui, Hongjuan

doi:10.1038/s41420-022-00976-9

Cited by 14 publications

(10 citation statements)

References 25 publications

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“…A recent study of non-tNC-derived tumor form glioblastoma identified that high MOXD1 expression associated with poor prognosis ( 45 ), which is opposite to our findings in NB. To explore the prognostic role of MOXD1 across cancer types, we therefore analyzed patient data from two additional non-tNC-derived tumor forms: breast and colon.…”

Section: Discussioncontrasting

confidence: 99%

MOXD1 is a gate-keeper of organ homeostasis and functions as a tumor-suppressor in neuroblastoma

Fredlund

Andersson

Hilgert

et al. 2023

Preprint

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Neuroblastoma is a childhood cancer believed to result from dysfunctional development. Its origin during embryogenesis remains poorly understood. The lack of appropriate models has hindered in-depth mapping of tumor-driving events. Here, we identify a novel tumor-suppressor gene that predicts poor survival in high-risk disease, by applying bulk and single cell RNA sequencing data of neuroblastoma and human fetal adrenal glands. Trunk neural crest-specific MOXD1 discriminates cell populations during normal and tumor development, with implications for deciphering neuroblastoma cell origin. We created an embryonic conditional knockout model and show that cell type-specific loss of MOXD1 leads to disrupted organ homeostasis and failed adrenal gland formation, home for neuroblastoma. We show that MOXD1 is a tumor suppressor gene in zebrafish, chick, and mice in vivo models.

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Section: Discussioncontrasting

confidence: 99%

MOXD1 is a gate-keeper of organ homeostasis and functions as a tumor-suppressor in neuroblastoma

Fredlund

Andersson

Hilgert

et al. 2023

Preprint

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“…Based on the public database, Xie and his colleagues identified MAP3K1 as a novel prognostic biomarker and potential therapeutic target in glioma ( 68 ). MOXD1 has also been predicted to enable copper ion–binding activity ( 69 ), and MOXD1 knockdown significantly suppresses the proliferation and tumor growth of glioblastoma cells via ER stress-inducing apoptosis ( 70 ). Accumulating evidence seems to indicate the potential roles of signature genes in glioma.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel cuproptosis-related gene signature and integrative analyses in patients with lower-grade gliomas

Bao

Duan

et al. 2022

Front. Immunol.

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BackgroundCuproptosis is a newly discovered unique non-apoptotic programmed cell death distinguished from known death mechanisms like ferroptosis, pyroptosis, and necroptosis. However, the prognostic value of cuproptosis and the correlation between cuproptosis and the tumor microenvironment (TME) in lower-grade gliomas (LGGs) remain unknown.MethodsIn this study, we systematically investigated the genetic and transcriptional variation, prognostic value, and expression patterns of cuproptosis-related genes (CRGs). The CRG score was applied to quantify the cuproptosis subtypes. We then evaluated their values in the TME, prognostic prediction, and therapeutic responses in LGG. Lastly, we collected five paired LGG and matched normal adjacent tissue samples from Sun Yat-sen University Cancer Center (SYSUCC) to verify the expression of signature genes by quantitative real-time PCR (qRT-PCR) and Western blotting (WB).ResultsTwo distinct cuproptosis-related clusters were identified using consensus unsupervised clustering analysis. The correlation between multilayer CRG alterations with clinical characteristics, prognosis, and TME cell infiltration were observed. Then, a well-performed cuproptosis-related risk model (CRG score) was developed to predict LGG patients’ prognosis, which was evaluated and validated in two external cohorts. We classified patients into high- and low-risk groups according to the CRG score and found that patients in the low-risk group showed significantly higher survival possibilities than those in the high-risk group (P<0.001). A high CRG score implies higher TME scores, more significant TME cell infiltration, and increased mutation burden. Meanwhile, the CRG score was significantly correlated with the cancer stem cell index, chemoradiotherapy sensitivity–related genes and immune checkpoint genes, and chemotherapeutic sensitivity, indicating the association with CRGs and treatment responses. Univariate and multivariate Cox regression analyses revealed that the CRG score was an independent prognostic predictor for LGG patients. Subsequently, a highly accurate predictive model was established for facilitating the clinical application of the CRG score, showing good predictive ability and calibration. Additionally, crucial CRGs were further validated by qRT-PCR and WB.ConclusionCollectively, we demonstrated a comprehensive overview of CRG profiles in LGG and established a novel risk model for LGG patients’ therapy status and prognosis. Our findings highlight the potential clinical implications of CRGs, suggesting that cuproptosis may be the potential therapeutic target for patients with LGG.

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“…This is in accordance to what is found in HCC livers as compared with periportal-HCC and normal livers [ 39 ]. Furthermore, it has been reported that the early growth response protein Egr1 and the copper-dependent monooxygenase Moxd1 , which were found to be significantly increased in NTBC-treated HT1 livers, are correlated to the invasiveness of HCC cells and early tumor development, respectively [ 41 , 42 ]. Expression of Moxd1 is also associated with poor survival in glioblastoma, whilst when it is downregulated, it activates ER-stress causing activation of the unfolded protein response.…”

Section: Discussionmentioning

confidence: 99%

Hereditary Tyrosinemia Type 1 Mice under Continuous Nitisinone Treatment Display Remnants of an Uncorrected Liver Disease Phenotype

Neuckermans

Lequeue

Claes

et al. 2023

Genes

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Hereditary tyrosinemia type 1 (HT1) is a genetic disorder of the tyrosine degradation pathway (TIMD) with unmet therapeutic needs. HT1 patients are unable to fully break down the amino acid tyrosine due to a deficient fumarylacetoacetate hydrolase (FAH) enzyme and, therefore, accumulate toxic tyrosine intermediates. If left untreated, they experience hepatic failure with comorbidities involving the renal and neurological system and the development of hepatocellular carcinoma (HCC). Nitisinone (NTBC), a potent inhibitor of the 4-hydroxyphenylpyruvate dioxygenase (HPD) enzyme, rescues HT1 patients from severe illness and death. However, despite its demonstrated benefits, HT1 patients under continuous NTBC therapy are at risk to develop HCC and adverse reactions in the eye, blood and lymphatic system, the mechanism of which is poorly understood. Moreover, NTBC does not restore the enzymatic defects inflicted by the disease nor does it cure HT1. Here, the changes in molecular pathways associated to the development and progression of HT1-driven liver disease that remains uncorrected under NTBC therapy were investigated using whole transcriptome analyses on the livers of Fah- and Hgd-deficient mice under continuous NTBC therapy and after seven days of NTBC therapy discontinuation. Alkaptonuria (AKU) was used as a tyrosine-inherited metabolic disorder reference disease with non-hepatic manifestations. The differentially expressed genes were enriched in toxicological gene classes related to liver disease, liver damage, liver regeneration and liver cancer, in particular HCC. Most importantly, a set of 25 genes related to liver disease and HCC development was identified that was differentially regulated in HT1 vs. AKU mouse livers under NTBC therapy. Some of those were further modulated upon NTBC therapy discontinuation in HT1 but not in AKU livers. Altogether, our data indicate that NTBC therapy does not completely resolves HT1-driven liver disease and supports the sustained risk to develop HCC over time as different HCC markers, including Moxd1, Saa, Mt, Dbp and Cxcl1, were significantly increased under NTBC.

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MOXD1 knockdown suppresses the proliferation and tumor growth of glioblastoma cells via ER stress-inducing apoptosis

Cited by 14 publications

References 25 publications

MOXD1 is a gate-keeper of organ homeostasis and functions as a tumor-suppressor in neuroblastoma

MOXD1 is a gate-keeper of organ homeostasis and functions as a tumor-suppressor in neuroblastoma

Identification of a novel cuproptosis-related gene signature and integrative analyses in patients with lower-grade gliomas

Hereditary Tyrosinemia Type 1 Mice under Continuous Nitisinone Treatment Display Remnants of an Uncorrected Liver Disease Phenotype

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