Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression

Tong, Yuru; Zhang, Zheng; Cheng, Yu-Rong; Yang, Jing; Fan, Cong; Zhang, Xuyang; Yang, Jiandong; Wang, Li; Guo, Dong; Yan, Dong

doi:10.1038/s41419-022-04779-9

Cited by 12 publications

(4 citation statements)

References 38 publications

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“…Five disease signature genes (NFATC3, ERMN, PLA2G4A, MTMR9LP and LOC440700) were screened and scored for a range of values for different genes to assess the probability of preterm infants with the disease. NFATC3 gene can inhibit or enhance cancer progression by inducing and modulating other pathways [ 50 – 52 ]. ERMN genes are mostly present in the expression profile of autistic patients [ 53 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of cuproptosis related genes and signature markers in bronchopulmonary dysplasia disease using bioinformatics analysis and machine learning

Jia

Zhang

et al. 2023

BMC Med Inform Decis Mak

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Background Bronchopulmonary Dysplasia (BPD) has a high incidence and affects the health of preterm infants. Cuproptosis is a novel form of cell death, but its mechanism of action in the disease is not yet clear. Machine learning, the latest tool for the analysis of biological samples, is still relatively rarely used for in-depth analysis and prediction of diseases. Methods and results First, the differential expression of cuproptosis-related genes (CRGs) in the GSE108754 dataset was extracted and the heat map showed that the expression of NFE2L2 gene was significantly higher in the control group whereas the expression of GLS gene was significantly higher in the treatment group. Chromosome location analysis showed that both the genes were positively correlated and associated with chromosome 2. The results of immune infiltration and immune cell differential analysis showed differences in the four immune cells, significantly in Monocytes cells. Five new pathways were analyzed through two subgroups based on consistent clustering of CRG expression. Weighted correlation network analysis (WGCNA) set the screening condition to the top 25% to obtain the disease signature genes. Four machine learning algorithms: Generalized Linear Models (GLM), Random Forest (RF), Support Vector Machine (SVM), and Extreme Gradient Boosting (XGB) were used to screen the disease signature genes, and the final five marker genes for disease prediction. The models constructed by GLM method were proved to be more accurate in the validation of two datasets, GSE190215 and GSE188944. Conclusion We eventually identified two copper death-associated genes, NFE2L2 and GLS. A machine learning model-GLM was constructed to predict the prevalence of BPD disease, and five disease signature genes NFATC3, ERMN, PLA2G4A, MTMR9LP and LOC440700 were identified. These genes that were bioinformatics analyzed could be potential targets for identifying BPD disease and treatment.

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Section: Discussionmentioning

confidence: 99%

Identification and validation of cuproptosis related genes and signature markers in bronchopulmonary dysplasia disease using bioinformatics analysis and machine learning

Jia

Zhang

et al. 2023

BMC Med Inform Decis Mak

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“…NFATc3 is a member of the NFAT family of transcription factors, which is involved in the regulation of processes such as apoptosis and cell cycle progression. Hypoxia-induced NFATc3 deSUMOylation has also been proven to be activated in cancer development and progression [34]. Coincidentally, RAG1 had once been reported to generate comparable levels of DSB in the episomal substrates [35].…”

Section: Discussionmentioning

confidence: 99%

Arsenic Sulfide EnhancesRadiosensitization in Rhabdomyosarcoma via Activating NFATc3-RAG1 Mediated DNA Double Strand Break (DSB)

Cai

Zhu

et al. 2023

Preprint

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Background: Due to the high level of recurrence and metastasis, rhabdomyosarcoma (RMS) represents one of the most lethal soft-tissue sarcomas in children. It is thus imperative to explore a novel radiosensitizer to enhance the curative of radiotherapy in RMS patients. The trace element arsenic has been reported to function as a radiosensitizer in sarcomas. To determine whether arsenic sulfide (As4S4) potentiates radiation sensitization in RMS, we carried out this study to investigate the mechanism of As4S4 in radiotherapy. Methods: RMS cell line (A-673) was treated with As4S4 and radiotherapy. Cell viability and drug-induced apoptosis were detected by cell counting kit-8 (CCK-8) and flow cytometry, respectively. Western blot and real-time qPCR were carried out to detect the nuclear factor of activated T-cells 3 (NFATc3) and recombination activating 1 (RAG1). DNA damage-associated proteins were also determined. For in vivo experiments, the therapeutic efficacy of As4S4-induced radiosensitization was evaluated via xenograft tumors in mice. To identify NFATc3 and RAG1, which were mostly involved in the mechanism of radiosensitization, we established a clinical cohort of 59 RMS patients. Immunohistochemistry (IHC) staining was applied to detect the expression of NFATc3 and RAG1 in RMS tissues in order to analyze the relationship with prognosis. We further developed a prediction model using stepwise logistic regression. Results: As4S4 combined with radiotherapy exhibited predominant inhibition in RMS cells through CCK-8 and flow cytometry. We revealed that As4S4 as well as the knockdown of NFATc3 resulted in DSB in RMS cells by the increased expression of RAG1. Our in vivo experiment confirmed that co-treatment exerted efficient inhibition of RMS growth. In a clinical cohort of 59 RMS patients, survival analysis showed that NFATc3 and RAG1 were related to overall survival (OS). Cox regression analysis further indicated that NFATc3, RAG1, and Risk level could be regarded as independent prognostic factors for RMS patients. Conclusions: In summary, As4S4 enhances radiosensitization in RMS via activating NFATc3-RAG1 mediated DNA DSB. NFATc3 and RAG1 are potential therapeutic targets in treating RMS. Our findings led us to conclude that As4S4 could be considered a radio-sensitizing agent for treating RMS.

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“…For each of two independent sample set, 10 human samples (5 tumor and 5 paracancerous tissues) were stained simultaneously. IHC scores were determined as described previously (Tong et al, 2022). The intensity of the ARAP1 signal was scored according to a four-point scale: 0 (no staining), 1 (weak light yellow staining), 2 (moderate yellow-brown staining), and 3 (strong brown staining).…”

Section: Methodsmentioning

confidence: 99%

GTPase-activating protein ARAP1 regulates circular dorsal ruffles as a nutrient uptake mechanism in the Hep3B hepatocellular carcinoma cell line

Sun,

Li,

et al. 2024

Preprint

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Circular dorsal ruffles (CDRs), large-scale rounded membrane ruffles, function as precursors of macropinocytosis. We recently reported that CDRs are exposed in the Hep3B hepatocellular carcinoma cell line, while not in other hepatocellular carcinoma cell lines, indicating that the CDRs in Hep3B are associated with malignant potential. In this study, we investigated the cellular function of CDRs in Hep3B cells by focusing on the molecular mechanisms of the GTPase-activating protein ARAP1. ARAP1 was localized to the CDRs, the sizes of which were reduced by deletion of this protein. High-resolution scanning electron micrographs revealed that CDRs comprise small vertical lamellipodia, the expression pattern of which was disrupted in ARAP1 KO cells. Extracellular solute uptake, rate of cell growth, and malignant potential were attenuated in the KO cells. ARAP1 is also localized in Hep3B cell mitochondria, although not in those of the Huh7 hepatocellular carcinoma cell line. On the basis of these findings, we propose that the aberrant expression of ARAP1 in Hep3B cells modulates CDRs, thereby resulting in an excess uptake of nutrients as an initial event in cancer development.SUMMARY STATEMENTARAP1 regulates circular dorsal ruffles (CDRs) in the Hep3B HCC cell line and deletion of this protein attenuates malignant potential, thereby indicating the involvement of CDRs in cancer development.

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Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression

Cited by 12 publications

References 38 publications

Identification and validation of cuproptosis related genes and signature markers in bronchopulmonary dysplasia disease using bioinformatics analysis and machine learning

Identification and validation of cuproptosis related genes and signature markers in bronchopulmonary dysplasia disease using bioinformatics analysis and machine learning

Arsenic Sulfide EnhancesRadiosensitization in Rhabdomyosarcoma via Activating NFATc3-RAG1 Mediated DNA Double Strand Break (DSB)

GTPase-activating protein ARAP1 regulates circular dorsal ruffles as a nutrient uptake mechanism in the Hep3B hepatocellular carcinoma cell line

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