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1.
Interdiscip Sci ; 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34495484

RESUMO

Inferring gene regulatory networks (GRNs) from microarray data can help us understand the mechanisms of life and eventually develop effective therapies. Currently, many computational methods have been used in inferring GRNs. However, owing to high-dimensional data and small samples, these methods often tend to introduce redundant regulatory relationships. Therefore, a novel network inference method based on the improved Markov blanket discovery algorithm, IMBDANET, is proposed to infer GRNs. Specifically, for each target gene, data processing inequality was applied to the Markov blanket discovery algorithm for the accurate differentiation of direct regulatory genes from indirect regulatory genes. Finally, direct regulatory genes were used in constructing GRNs, and the network structure was optimized according to the importance degree score. Experimental results on six public network datasets show that the proposed method can be effectively used to infer GRNs.

2.
J Exp Clin Cancer Res ; 40(1): 284, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34496932

RESUMO

BACKGROUND: Chemotherapy resistance remains a barrier to improving the prognosis of epithelial ovarian cancer (EOC). ALKBH5 has recently been shown to be one of the RNA N6-methyladenosine (m6A) demethyltransferases associated with various cancers, but its role in cancer therapeutic resistance remains unclear. This study aimed to investigate the role of AlkB homolog 5 (ALKBH5) in cisplatin-resistant EOC. METHODS: Functional assays were performed both in vitro and in vivo. RNA sequencing (RNA-seq), m6A-modified RNA immunoprecipitation sequencing (MeRIP-seq), chromatin immunoprecipitation, RNA immunoprecipitation, and luciferase reporter and actinomycin-D assays were performed to investigate RNA/RNA interaction and m6A modification of the ALKBH5-HOXA10 loop. RESULTS: ALKBH5 was upregulated in cisplatin-resistant EOC and promoted cancer cell cisplatin resistance both in vivo and in vitro. Notably, HOXA10 formed a loop with ALKBH5 and was found to be the upstream transcription factor of ALKBH5. HOXA10 overexpression also facilitated EOC cell chemoresistance both in vivo and in vitro. Collective results of MeRIP-seq and RNA-seq showed that JAK2 is the m6A-modified gene targeted by ALKBH5. The JAK2/STAT3 signaling pathway was activated by overexpression of the ALKBH5-HOXA10 loop, resulting in EOC chemoresistance. Cell sensitivity to cisplatin was rescued by ALKBH5 and HOXA10 knockdown or inhibition of the JAK2/STAT3 signaling pathway in EOC cells overexpressing ALKBH5-HOXA10. CONCLUSIONS: The ALKBH5-HOXA10 loop jointly activates the JAK2/STAT3 signaling pathway by mediating JAK2 m6A demethylation, promoting EOC resistance to cisplatin. Thus, inhibition of the expression of the ALKBH5-HOXA10 loop may be a potential strategy to overcome cisplatin resistance in EOC.

5.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(9): 877-881, 2021.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34535200

RESUMO

OBJECTIVES: To study the efficacy of Huaiqihuang granules as adjuvant therapy for bronchial asthma in children. METHODS: A multicenter, prospective, and registered real-world study was performed for the children, aged 2-5 years, who had a confirmed diagnosis of bronchial asthma in the outpatient service of 21 hospitals in China. Among these children, the children treated with medications for long-term asthma control (inhaled corticosteroid and/or leukotriene receptor antagonist) without Huaiqihuang granules were enrolled as the control treatment group, and those treated with medications for long-term asthma control combined with Huaiqihuang granules were enrolled as the combined treatment group. The medical data of all children were collected. Outpatient or telephone follow-up was performed at weeks 4, 8, 12, 20, 28, and 36 after treatment, including asthma attacks and rhinitis symptoms. A statistical analysis was performed for the changes in these indices. RESULTS: There was no significant difference in the frequency of asthma attacks or rhinitis attacks between the two groups before treatment (P>0.05). After treatment, the combined treatment group had significantly lower frequencies of asthma attacks, severe asthma attacks, and rhinitis attacks compared with the control treatment group (P<0.05). There was no signification difference in the incidence rate of adverse reactions between the two groups (P=0.667). CONCLUSIONS: Huaiqihuang granules in addition to medications for long-term asthma control can alleviate the symptoms of bronchial asthma and rhinitis and improve the level of asthma control in children with bronchial asthma, with good safety and little adverse effect. Citation.


Assuntos
Asma , Medicamentos de Ervas Chinesas , Asma/tratamento farmacológico , Criança , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Estudos Prospectivos , Qualidade de Vida
6.
Nat Struct Mol Biol ; 28(9): 755-761, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34518695

RESUMO

Bradykinin and kallidin are endogenous kinin peptide hormones that belong to the kallikrein-kinin system and are essential to the regulation of blood pressure, inflammation, coagulation and pain control. Des-Arg10-kallidin, the carboxy-terminal des-Arg metabolite of kallidin, and bradykinin selectively activate two G protein-coupled receptors, type 1 and type 2 bradykinin receptors (B1R and B2R), respectively. The hyperactivation of bradykinin receptors, termed 'bradykinin storm', is associated with pulmonary edema in COVID-19 patients, suggesting that bradykinin receptors are important targets for COVID-19 intervention. Here we report two G protein-coupled complex structures of human B1R and B2R bound to des-Arg10-kallidin and bradykinin, respectively. Combined with functional analysis, our structures reveal the mechanism of ligand selectivity and specific activation of the bradykinin receptor. These findings also provide a framework for guiding drug design targeting bradykinin receptors for the treatment of inflammation, cardiovascular disorders and COVID-19.

7.
Clin Breast Cancer ; 2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34548240

RESUMO

Hormone replacement therapy (HRT) is associated with increased risk of breast cancer (BC), but little evidence assesses the effects of potential effect-modifiers on HRT-related BC. We sought to examine the relationship of different HRT types/method use and risk of BC in US postmenopausal women. In total, 689 BC cases and 81 BC deaths were identified during 372,210 person-years of follow-up. Cox regression and competing risk regression were used to estimate multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (95% CIs) by HRT status (never, former, current) for risk of BC incidence and mortality. The total current HRT use was associated with an increased risk of BC (HR current vs. never, 1.67; 95% CI, 1.33, 2.11), but did not associate with risk of death from BC (HR current vs. never, 0.85; 95% CI, 0.40, 1.78). Furthermore, underweight women (BMI <20 kg/m2, HR current vs. never, 12.05, 95% CI, 1.46, 99.75) were more likely to take increased risk of BC from HRT use compared to the obese (BMI >30 kg/m2, HR current vs never, 1.19; 95% CI, 0.73, 1.97). This study suggests that HRT use was associated with an altered risk of the occurrence of BC in the US postmenopausal women, especially for underweight women.

8.
Sci Rep ; 11(1): 18766, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34548616

RESUMO

Throughout the world, esophageal cancer patients had a greater suicidal risk compared with ordinary people. Thus, we aimed to affirm suicide rates, standardized mortality rates, and underlying suicide-related risk factors of esophageal cancer patients. Patients suffering esophageal cancer were chosen from the Surveillance, Epidemiology, and End Results repository in 1975-2016. Suicide rates as well as standardized mortality rates in the patients were measured. Univariable and multivariable Cox regression had been adopted for establishing the latent suicide risk factors among patients suffering esophageal cancer. On multivariable Cox regression, gender (male vs. female, HR: 6.37), age of diagnosis (70-105 vs. 0-55, HR: 2.69), marital status, race (white race vs. black race, HR: 6.64; American Indian/Alaska Native, Asian/Pacific Islander vs. black race, HR: 8.60), histologic Grade (Grade III vs. Grade I, HR: 2.36), no surgery performed (no/unknown vs. yes, HR: 2.01), no chemotherapy performed were independent risk factors related to suicide in patients suffering esophageal cancer. Male sex, the older age, unmarried state, non-black race, histologic Grade III, no surgery performed, no chemotherapy performed were strongly related to suicide in patients suffering esophageal cancer.

9.
JCI Insight ; 6(18)2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34549727

RESUMO

Aiming to identify rare high-penetrance mutations in new genes for the underlying predisposition in familial colorectal cancer (CRC), we performed whole-exome sequencing in 24 familial CRCs. Mutations in genes that regulate DNA repair (RMI1, PALB2, FANCI) were identified that were related to the Fanconi anemia DNA repair pathway. In one pedigree, we found a nonsense mutation in CHEK2. CHEK2 played an essential role in cell cycle and DNA damage repair. Somatic mutation analysis in CHEK2 variant carriers showed mutations in TP53, APC, and FBXW7. Loss of heterozygosity was found in carcinoma of CHEK2 variant carrier, and IHC showed loss of Chk2 expression in cancer tissue. We identified a second variant in CHEK2 in 126 sporadic CRCs. A KO cellular model for CHEK2 (CHEK2KO) was generated by CRISPR/Cas9. Functional experiments demonstrated that CHEK2KO cells showed defective cell cycle arrest and apoptosis, as well as reduced p53 phosphorylation, upon DNA damage. We associated germline mutations in genes that regulate the DNA repair pathway with the development of CRC. We identified CHEK2 as a regulator of DNA damage response and perhaps as a gene involved in CRC germline predisposition. These findings link CRC predisposition to the DNA repair pathway, supporting the connection between genome integrity and cancer risk.

10.
Nature ; 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34552239

RESUMO

Luteinizing hormone and chorionic gonadotropin are glycoprotein hormones that are related to follicle-stimulating hormone and thyroid-stimulating hormone1,2. Luteinizing hormone and chorionic gonadotropin are essential to human reproduction and are important therapeutic drugs3-6. They activate the same G-protein-coupled receptor, luteinizing hormone-choriogonadotropin receptor (LHCGR), by binding to the large extracellular domain3. Here we report four cryo-electron microscopy structures of LHCGR: two structures of the wild-type receptor in the inactive and active states; and two structures of the constitutively active mutated receptor. The active structures are bound to chorionic gonadotropin and the stimulatory G protein (Gs), and one of the structures also contains Org43553, an allosteric agonist7. The structures reveal a distinct 'push-and-pull' mechanism of receptor activation, in which the extracellular domain is pushed by the bound hormone and pulled by the extended hinge loop next to the transmembrane domain. A highly conserved 10-residue fragment (P10) from the hinge C-terminal loop at the interface between the extracellular domain and the transmembrane domain functions as a tethered agonist to induce conformational changes in the transmembrane domain and G-protein coupling. Org43553 binds to a pocket of the transmembrane domain and interacts directly with P10, which further stabilizes the active conformation. Together, these structures provide a common model for understanding the signalling of glycoprotein hormone receptors and a basis for drug discovery for endocrine diseases.

11.
J Ovarian Res ; 14(1): 115, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34474677

RESUMO

Tumor microenvironment and chemokines play a significant role in cancer chemoresistance. This study was designed to reveal the important role of CXCL2 in platinum resistance in epithelial ovarian cancer (EOC). Differently expressed (DE) genes were screen out based on analysis of GSE114206 dataset in GEO database. The expression of DE chemokines was further validated in platinum- resistant and sensitive EOC. Cell viability assay and cell apoptosis assay were performed to explore the roles of CXCL2 in EOC. Cell stemness characteristics and the signaling pathway regulated by CXCL2 were also investigated in this study. As the results showed, CXCL2 was identified up-regulated in platinum-resistant EOC. The functional assays showed overexpressing CXCL2 or co-culturing with recombinant human CXCL2 promoted cell resistance to cisplatin. Conversely, knocking down CXCL2 or co-culturing with neutralizing antibody to CXCL2 increased cell response to cisplatin. CXCL2 overexpressing maintained cell stemness and activated ATR/CHK1 signaling pathway in EOC. Moreover, we further demonstrated that CXCL2-mediated resistance to cisplatin could be saved by SB225002, the inhibitor of CXCL2 receptor, as well as be rescued by SAR-020106, the inhibitor of ATR/CHK1 signaling pathway. This study identified a CXCL2-mediated mechanism in EOC platinum resistance. Our findings provided a novel target for chemoresistance prevention in EOC.

12.
Trials ; 22(1): 585, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479619

RESUMO

BACKGROUND: Major depressive disorder is the second leading cause of years lost to disability worldwide. Anyu Peibo Capsule has been shown to be effective and safe in phase II trials. METHODS: This clinical study is a multi-center, randomized, double-blinded, placebo-controlled, parallel-group, phase III trial of Anyu Peibo Capsule in China. The aim is to test whether the administration of Anyu Peibo Capsule compared to placebo improves clinical outcomes in adults (aged 18 to 65 years) with MDD. Patients will receive an 8-week treatment of Anyu Peibo Capsule 1.6 g per day or placebo. The primary outcome will be the change from baseline in the total score for the Montgomery-Asberg Depression Rating Scale at the end of the 8-week treatment. DISCUSSION: The trial aims to provide pivotal evidence for the efficacy and safety of Anyu Peibo Capsule in patients with major depressive disorder. TRIAL REGISTRATION: ClinicalTrials.gov NCT04210973 . Registered on December 26, 2019.


Assuntos
Transtorno Depressivo Maior , Adulto , China , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Método Duplo-Cego , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
13.
Immunol Invest ; : 1-14, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34503373

RESUMO

Alzheimer's disease (AD) is a prevalent type of dementia and threatens the health of most elderly people and poses a huge burden to families and society. The fibroblast growth factor 23 (FGF23)/α-Klotho axis is associated with multiple aging-related diseases. Hence, this study explored the mechanism of the FGF23/α-Klotho axis in AD. FGF23/α-Klotho protein contents and levels of inflammatory cytokines in AD patients were measured, and the correlation between FGF23/α-Klotho protein contents and inflammatory cytokines was analyzed. FGF23 and α-Klotho expressions were blocked in peripheral blood mononuclear cells (PBMCs) in AD patients (AD-PBMCs) to assess the effects on cell inflammation and the Wnt/ß-catenin pathway activation. The Wnt/ß-catenin pathway was inhibited to evaluate cell inflammation. Combined treatments of the cells were conducted to verify the role of the FGF23/α-Klotho axis and the Wnt/ß-catenin pathway in inflammation in AD-PBMCs. Increased FGF23 protein concentration and reduced α-Klotho protein concentration were observed in AD patients and correlated with inflammatory cytokine levels. FGF23 inhibition or α-Klotho overexpression reduced the production of inflammatory cytokines and activated the Wnt/ß-catenin pathway in AD-PBMCs. Blocking the Wnt/ß-catenin pathway increased inflammatory cytokine production in AD-PBMCs and annulled the effects of the FGF23/α-Klotho axis on AD-induced cell inflammation. We concluded that the FGF23/α-Klotho axis can regulate the AD-induced cell inflammation through the Wnt/ß-catenin pathway.

14.
Analyst ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34505605

RESUMO

In this work, metal-organic frameworks (MOFs) are utilized as effective ECL coreactant accelerator to enhance the ECL responses of N-(aminobutyl)-N-(ethylisoluminol) (ABEI). Zn-based MOFs (MOF-Zn-1) were prepared by chelating Zn ions with melamine and thiophenedicarboxylic acid (TPDA), which observably accelerated the electrocatalytic oxidation of tripropylamine (TPA). Then, ABEI-MOF-Zn-1 as a high-performance ECL emitter was synthesized via an amide reaction between ABEI and mercaptopropionic acid (MPA) modified MOF-Zn-1. Strikingly, the ABEI-MOF-Zn-1 showed the 18-fold increase in the ECL signals relative to pure ABEI by using TPA as a coreactant. Moreover, ferrocene (Fc) as a quencher was first linked with capture DNA (cDNA), and then used to modify the ABEI-MOF-Zn-1, thereby constructing a label-free ECL biosensor. After the linkage between chloramphenicol (CAP) and aptamer DNA (aptDNA), the ECL response was definitely recovered by releasing L-DNA from double-stranded DNA (dsDNA, hybridization of aptDNA and L-DNA). The resultant sensor showed a wide linear range of 1.00 nM-0.10 mM (R2 = 0.99) and a low limit of detection (LOD) down to 0.11 nM for detecting CAP. This work developed a novel pattern to design an efficient ECL enhanced emitter, coupled by expanding its potential applications in clinical diagnosis.

15.
Alzheimer Dis Assoc Disord ; 35(3): 278-288, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34432674

RESUMO

OBJECTIVE: The purpose of this meta-analysis was to evaluate the beneficial effects and optimal stimulation protocol of noninvasive brain stimulation (NIBS) including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on patients with mild cognitive impairment and Alzheimer disease. MATERIALS AND METHODS: PubMed, Web of Science, Embase, and the Cochrane Library were searched until March 2020. The cognitive outcomes were extracted and the standardized mean difference with 95% confidence interval was calculated. RESULTS: Twenty-eight studies were included. The result of NIBS showed significant effect on global cognition (P<0.05). Low-frequency rTMS over right dorsolateral prefrontal cortex (DLPFC), high-frequency rTMS (HF-rTMS) over left DLPFC, and the tDCS over left DLPFC and temporal lobe can significantly improve the memory function (P<0.05). HF-rTMS over left, right, or bilateral DLPFC can significantly improve the language function (P<0.05). Both HF-rTMS and tDCS over left DLPFC can obviously improve the executive function (P<0.05). Multiple sessions of rTMS with 80% to 100% intensity and anode tDCS with 2 mA current density are more suitable for all these functions. CONCLUSIONS: NIBS has a beneficial effect on cognitive performance in both mild cognitive impairment and Alzheimer disease patients. Distinct optimal stimulation parameters were observed for different cognitive functions.

16.
Cell Res ; 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34453129

RESUMO

Melanocortins are peptide hormones critical for the regulation of stress response, energy homeostasis, inflammation, and skin pigmentation. Their functions are mediated by five G protein-coupled receptors (MC1R-MC5R), predominately through the stimulatory G protein (Gs). MC1R, the founding member of melanocortin receptors, is mainly expressed in melanocytes and is involved in melanogenesis. Dysfunction of MC1R is associated with the development of melanoma and skin cancer. Here we present three cryo-electron microscopy structures of the MC1R-Gs complexes bound to endogenous hormone α-MSH, a marketed drug afamelanotide, and a synthetic agonist SHU9119. These structures reveal the orthosteric binding pocket for the conserved HFRW motif among melanocortins and the crucial role of calcium ion in ligand binding. They also demonstrate the basis of differential activities among different ligands. In addition, unexpected interactions between MC1R and the Gß subunit were discovered from these structures. Together, our results elucidate a conserved mechanism of calcium-mediated ligand recognition, a specific mode of G protein coupling, and a universal activation pathway of melanocortin receptors.

17.
BMC Nephrol ; 22(1): 289, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433442

RESUMO

BACKGROUND: Acute kidney injury (AKI) newly-emerged in intensive care unit (ICU), has not been thoroughly studied in previous researches, is likely to differ from AKI developed before ICU admission. This study aimed to evaluate the incidence, risk factors, clinical features and outcome of new-onset AKI in critically ill patients. METHODS: The data of present study derived from a multicenter, prospective cohort study in17 Chinese ICUs (January 2014 - August 2015). The incidence, risk factors, clinical features and survival analysis of new-onset AKI were assessed. RESULTS: A total of 3374 adult critically ill patients were eligible. The incidence of new-onset AKI was 30.0 % (n = 1012). Factors associated with a higher risk of new-onset AKI included coronary heart disease, hypertension, chronic liver disease, use of nephrotoxic drugs, sepsis, SOFA score, APACHEII score and use of vasopressors. The new-onset AKI was an independent risk factor for 28-day mortality (adjusted hazard ratio, 1.643; 95 % CI, 1.370-1.948; P < 0.001). 220 (21.7 %) patients received renal replacement therapy (RRT), 71 (32.3 %) of them were successfully weaning from RRT. More than half of the new-onset AKI were transient AKI (renal recovery within 48 h). There was no statistical relationship between transient AKI and 28-day mortality (hazard ratio, 1.406; 95 % CI, 0.840-1.304; P = 0.686), while persistent AKI (non-renal recovery within 48 h) was strongly associated with 28-day mortality (adjusted hazard ratio, 1.486; 95 % CI, 1.137-1.943; P < 0.001). CONCLUSIONS: New-onset AKI is common in ICU patients and is associated with significantly higher 28-day mortality. Only persistent AKI, but not transient AKI is associated with significantly higher 28-day mortality.

18.
Genes (Basel) ; 12(8)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34440334

RESUMO

Maintaining genomic stability is vital for cells as well as individual organisms. The meiotic recombination-related gene MRE11 (meiotic recombination 11) is essential for preserving genomic stability through its important roles in the resection of broken DNA ends, DNA damage response (DDR), DNA double-strand breaks (DSBs) repair, and telomere maintenance. The post-translational modifications (PTMs), such as phosphorylation, ubiquitination, and methylation, regulate directly the function of MRE11 and endow MRE11 with capabilities to respond to cellular processes in promptly, precisely, and with more diversified manners. Here in this paper, we focus primarily on the PTMs of MRE11 and their roles in DNA response and repair, maintenance of genomic stability, as well as their association with diseases such as cancer.

19.
J Stroke Cerebrovasc Dis ; 30(10): 106045, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34418671

RESUMO

BACKGROUND: Matrix metalloproteinase 10 (MMP-10) has a close relationship with carotid atherosclerosis (CAS) and cerebral infarction. The MMP-10 rs17435959 polymorphism causes a leucine to valine transition at codon 4 in exon 1 of the MMP-10 gene and may have functional effects. OBJECTIVES: To investigate the relationship between the MMP-10 rs17435959 polymorphism and the formation and stability of CAS plaques. MATERIALS AND METHODS: The present case-control study contains 738 visitors who came to our health examination center for the first time. According to the carotid ultrasound examinations, visitors were classified into the vulnerable plaque group (41-86 years old, 141 male, 105 female), the stable plaque group (41-86 years old, 141 male, 105 female) and the no plaque group (41-85 years old, 141 male, 105 female). All visitors in the three groups were sex- and- age-matched, and cardiovascular and cerebrovascular diseases were absent. The polymorphism was genotyped by real-time polymerase chain reaction- restriction. RESULTS: Compared to the GG genotype, the frequency of the CC and CG genotypes was significantly more common in the vulnerable plaque group than in the no plaque group (18.7% vs. 7.7%, unadjusted P = 0.002). Moreover, compared to the G allele, the frequency of the C allele was significantly more common in the vulnerable plaque group than in the no plaque group (10.4% vs. 3.9%, unadjusted P = 0.000) and in the vulnerable plaque group than in the stable plaque group (10.4% vs. 5.1%, unadjusted P = 0.008). Binary logistic regression showed that the CC and CG genotype was independent risk factor for the formation (P = 0.019, OR = 1.961, 95% CI [1.117, 3.444]) and vulnerability (P = 0.035, OR = 1.842, 95% CI [1.045, 3.247]) of CAS plaques. Moreover, individuals who have the C allele showed a higher level of fibrinogen, which was an independent risk factor for the formation of CAS plaques (P = 0.000, OR = 2.425, 95% CI [1.475, 3.985]). CONCLUSIONS: The rs17435959 polymorphism was associated with the formation and vulnerability of CAS plaques. Individuals who had variant-type MMP-10 showed higher levels of fibrinogen, which promoted the formation of CAS plaques.

20.
Cancer Res ; 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408002

RESUMO

Genomic alterations are crucial for the development and progression of human cancers. Copy number gains found in genes encoding metabolic enzymes may induce triple-negative breast cancer (TNBC) adaptation. However, little is known about how metabolic enzymes regulate TNBC metastasis. Using our previously constructed multiomic profiling of a TNBC cohort, we identified decaprenyl diphosphate synthase subunit 1 (PDSS1) as an essential gene for TNBC metastasis. PDSS1 expression was significantly upregulated in TNBC tissues compared to adjacent normal tissues and was positively associated with poor survival among TNBC patients. PDSS1 knockdown inhibited TNBC cell migration, invasion, and distant metastasis. Mechanistically, PDSS1, but not a catalytically inactive mutant, positively regulated the cellular level of coenzyme Q10 (CoQ10) and intracellular calcium levels, thereby inducing CAMK2A phosphorylation, which is essential for STAT3 phosphorylation in the cytoplasm. Phosphorylated STAT3 entered the nucleus, promoting oncogenic STAT3 signaling and TNBC metastasis. STAT3 phosphorylation inhibitors (e.g., Stattic) effectively blocked PDSS1-induced cell migration and invasion in vitro and tumor metastasis in vivo. Taken together, our study highlights the importance of targeting the previously uncharacterized PDSS1/CAMK2A/STAT3 oncogenic signaling axis, expanding the repertoire of precision medicine in TNBC.

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