IRF1-mediated downregulation of PGC1α contributes to cardiorenal syndrome type 4

Huang, Yinghui; Wang, Shaobo; Zhou, Jie; Liu, Yong; Du, Changhong; Yang, Kang; Bi, Xianjin; Liu, Mingying; Han, Wenhao; Wang, Kailong; Xiong, Jiachuan; Wang, Song; Wang, Yue; Nie, Lei; Liu, Chi; Zhang, Daohai; Gu, Jun; Zeng, Chunyu; Zhao, Jinghong

doi:10.1038/s41467-020-18519-0

Cited by 47 publications

(62 citation statements)

References 52 publications

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“…In accordance with the manufacturer’s instructions, total RNA from the above mentioned 60 tissue samples was extracted using TRIzol Reagent (Invitrogen, United States), and the OD260/OD280 of RNA was detected using a NanoDrop 2000 spectrophotometer (Thermo Fisher Scientific, United States). Only when the OD260/OD280 of RNA was between 1.8 and 2.0, was the RNA used for subsequent reverse transcription with a reverse transcription kit (FSQ-301, Toyobo, Japan) ( Huang et al, 2020 ). Reverse transcription was performed in a 10-μL reaction volume using the Applied Biosystems 7500 Real-time PCR system with SYBR Green Real-time PCR Master Mix (QPK-201, Toyobo, Japan).…”

Section: Methodsmentioning

confidence: 99%

Identification and Validation of a Six Immune-Related Genes Signature for Predicting Prognosis in Patients With Stage II Colorectal Cancer

Xie

Yin

et al. 2021

Front. Genet.

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BackgroundImmune-related genes (IRGs) play important roles in the tumor immune microenvironment and can affect the prognosis of cancer. This study aimed to construct a novel IRG signature for prognostic evaluation of stage II colorectal cancer (CRC).MethodsGene expression profiles and clinical data for stage II CRC patients were collected from the Cancer Genome Atlas and Gene Expression Omnibus database. Univariate, multivariate Cox regression, and least absolute shrinkage and selection operator regression were used to develop the IRG signature, namely IRGCRCII. A nomogram was constructed, and the “Cell Type Identification by Estimating Relative Subsets of RNA Transcripts” (CIBERSORT) method was used to estimate immune cell infiltration. The expression levels of genes and proteins were validated by qRT-PCR and immunohistochemistry in 30 pairs of primary stage II CRC and matched normal tissues.ResultsA total of 466 patients with stage II CRC were included, and 274 differentially expressed IRGs were identified. Six differentially expressed IRGs were detected and used to construct the IRGCRCII signature, which could significantly stratify patients into high-risk and low-risk groups in terms of disease-free survival in three cohorts: training, test, and external validation (GSE39582). Receiver operating characteristics analysis revealed that the area under the curves of the IRGCRCII signature were significantly greater than those of the OncotypeDX colon signature at 1 (0.759 vs. 0.623), 3 (0.875 vs. 0.629), and 5 years (0.906 vs. 0.698) disease-free survival, respectively. The nomogram performed well in the concordance index (0.779) and calibration curves. The high-risk group had a significantly higher percentage of infiltrated immune cells (e.g., M2 macrophages, plasma cells, resting mast cells) than the low-risk group. Finally, the results of qRT-PCR and immunohistochemistry experiments performed on 30 pairs of clinical specimens were consistent with bioinformatics analysis.ConclusionThis study developed and validated a novel immune prognostic signature based on six differentially expressed IRGs for predicting disease-free survival and immune status in patients with stage II CRC, which may reflect immune dysregulation in the tumor immune microenvironment.

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Section: Methodsmentioning

confidence: 99%

Identification and Validation of a Six Immune-Related Genes Signature for Predicting Prognosis in Patients With Stage II Colorectal Cancer

Xie

Yin

et al. 2021

Front. Genet.

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“…Traditional risk factors [ 49 ], unfortunately, are insufficient to completely explain the high prevalence of cardiac death in children from 0 to 19 years old on dialysis or transplanted [ 50 , 51 , 52 ]. In these patients, the complications leading to death may be linked also to uremia-related risk factors [ 6 ]. A cross-sectional investigation of all pediatric maintenance hemodialysis patients (aged 0.7–18 years, n = 656) revealed that 38% have anemia, 63% have serum phosphorus >5.5 mg/dL, and 55% have a calcium–phosphorus product >55 mg 2 /dL 2 [ 53 ].…”

Section: Crs Typementioning

confidence: 99%

“…Huang et al recently demonstrated in an experimental study that a uremic molecule, known as high phosphate (HP), contributes to CKD-associated HF [ 6 ]. HP is crucial in the impairment of myocardial energy metabolism function by inducing alterations in the transcriptional factor interferon regulatory factor 1 (IRF1)–peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1a) signaling pathway.…”

Section: Crs Typementioning

confidence: 99%

“…Huang et al demonstrated that myocardial energy metabolism dysfunction induced by the IRF1-PGC1α axisplays a crucial role in the pathogenesis of type 4 CRS and suggested that hyperphosphatemia management or targeted intervention on HP-mediated IRF1 elevation and PGC1α downregulation could represent a future treatment able to reduce cardiovascular risk in CKD patients [ 6 ].…”

Section: Crs Typementioning

confidence: 99%

“…In recent years, next-generation sequencing technologies, including exome and mRNA sequencing studies, have shed new light on the complex molecular mechanisms underlying CRS [ 4 , 5 ]. This has led to a better understanding of the intricate subcellular mechanisms underlying these conditions and promoting the risk of both CRS and CVS, including several regulatory networks and transcriptional factors, such as the interferon regulatory factor 1 [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Update on the Classification and Pathophysiological Mechanisms of Pediatric Cardiorenal Syndromes

et al. 2021

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Cardiorenal syndrome (CRS) is defined as a disorder resulting from the abnormal interaction between the heart and kidney, in which acute or chronic dysfunction of one organ may lead to acute and/or chronic dysfunction of the other. The functional interplay between the heart and kidney is characterized by a complex bidirectional symbiotic interaction, regulated by a wide array of both genetic and environmental mechanisms. There are at least five known subtypes of CRS, based on the severity of clinical features and the degree of heart/renal failure. The fourth subtype (cardiorenal syndrome type 4 (CRS4)) is characterized by a primary chronic kidney disease (CKD), which in turn leads to a decreased cardiac function. Impairment of renal function is among the most important pathophysiological factors contributing to heart failure (HF) in the pediatric age group, and cardiovascular complications could be one of the most important causes of mortality in pediatric patients with advanced CKD. In this context, a loss of glomerular filtration rate directly correlates with both the progression of cardiovascular complications in CRS and the risk of HF. This review describes the interaction pathways between the heart and kidney and the recently identified pathophysiological mechanisms underlying pediatric CRS, with a special focus on CRS4, which encompasses both primary CKD and cardiovascular disease (CVD).

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Nuclear export of BATF2 enhances colorectal cancer proliferation through binding to CRM1

Zhou

Lei

Chen

et al. 2023

Clinical & Translational Med

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Background During the tumourigenesis and development of colorectal cancer (CRC), the inactivation of tumour suppressor genes is closely involved, although detailed molecular mechanisms remain elusive. Accumulating studies, including ours, have demonstrated that basic leucine zipper transcription factor ATF (activating transcription factor)‐like 2 (BATF2) is a capable tumour suppressor that localises in the nucleus. However, its different subcellular localisation, potential functions and underlying mechanisms are unclear. Methods The translocation of BATF2 and its clinical relevance were detected using CRC samples, cell lines and xenograft nude mice. Candidate BATF2‐binding proteins were screened using co‐immunoprecipitation, quantitative label‐free liquid chromatography–tandem mass spectrometry proteomic analysis, Western blotting and immunofluorescence. Recombinant plasmids, point mutations and siRNAs were applied to clarify the binding sites between BATF2 and chromosome region maintenance 1 (CRM1). Results The present study found that BATF2 was mainly localised in the cytoplasm, rather than nucleus, of CRC cells in vitro and in vivo, while cytoplasmic BATF2 expression was inversely correlated with the prognosis of CRC patients. Furthermore, we identified the nuclear export and subsequent ubiquitin‐mediated degradation of BATF2 in CRC cells. Mechanistically, a functional nuclear export sequence (any amino acid) was characterised in BATF2 protein, through which BATF2 bound to CRM1 and translocated out of nucleus, ultimately enhancing CRC growth via inducing activator protein 1 (AP‐1)/cyclin D1/phosphorylated retinoblastoma protein (pRb) signalling pathway. Additionally, nuclear export of BATF2 can be retarded by the mutation of NES in BATF2 or the knockdown of CRM1, whereas CRM1 expression was negatively associated with nuclear BATF2 expression and the prognosis of CRC patients. Conclusion These findings revealed the biological effects and underlying mechanisms of cytoplasmic localisation of BATF2. Furthermore, suppressing nuclear export of BATF2 via mutating its NES region or inhibiting CRM1 expression may serve as a promising therapeutic strategy against CRC.

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IRF1-mediated downregulation of PGC1α contributes to cardiorenal syndrome type 4

Cited by 47 publications

References 52 publications

Identification and Validation of a Six Immune-Related Genes Signature for Predicting Prognosis in Patients With Stage II Colorectal Cancer

Identification and Validation of a Six Immune-Related Genes Signature for Predicting Prognosis in Patients With Stage II Colorectal Cancer

Update on the Classification and Pathophysiological Mechanisms of Pediatric Cardiorenal Syndromes

Nuclear export of BATF2 enhances colorectal cancer proliferation through binding to CRM1

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