The Clinical Outcomes and Genomic Landscapes of Acute Lymphoblastic Leukemia Patients with E2A-PBX1: A 10-year Retrospective Study.
The clinical outcomes and genomic features of E2A-PBX1 (TCF3-PBX1)-positive B-cell acute lymphoblastic leukemia (B-ALL) patients remain unclear. 137 patients carrying E2A-PBX1 among 3164 B-ALL patients between 2009 and 2019 were retrospectively analyzed. The 5-year overall survival (OS) and disease-free survival (DFS) rates of the whole cohort were 68.6% and 61.0%, respectively. Age (DFS: P=0.037; cumulative incidence of relapse (CIR): P=0.005) and the level of minimal residual disease (MRD) after induction chemotherapy (OS: P=0.020; DFS: P=0.002; CIR: P=0.006) were independent risk factors. In adolescents/adults, allogeneic hematopoietic stem cell transplantation (allo-HSCT) at CR1 significantly improved the 5-year prognosis (OS: P<0.001; DFS: P<0.001; CIR: P<0.001). Haploidentical-HSCT decreased the CIR compared with HLA-matched-HSCT in adolescents/adults (P=0.017). Mutations in PBX1, PAX5, CTCF and SETD2, amplification of AKT3, and deletion of CDKN2A/B were common in the total cohort, while transcriptome differences were found in the cell cycle, NGF signaling pathway and transcriptional regulation by TP53 between adolescents/adults and children. Patients with multiple subclones at diagnosis tended to have unfavorable 3-year prognoses (DFS: P=0.010; CIR: P=0.021). Leukemia clones with DNA repair gene mutations showed aggressive and treatment-refractory phenotypes in this subtype of ALL. Our study indicated that age, the level of MRD and DNA repair gene mutations were associated with E2A-PBX1-positive B-ALL outcomes. Allo-HSCT, especially haploidentical-HSCT, could improve the prognosis of adolescent/adult patients. This article is protected by copyright. All rights reserved.
Publication Date: 2021-08-19
Journal: American journal of hematology
A Comprehensive Comparison of Early-Onset and Average-Onset Colorectal Cancers.
The causative factors for the recent increase in early-onset colorectal cancer (EO-CRC) incidence are unknown. We sought to determine if early-onset disease is clinically or genomically distinct from average-onset colorectal cancer (AO-CRC).
Clinical, histopathologic, and genomic characteristics of EO-CRC patients (2014-2019), divided into age 35 years and younger and 36-49 years at diagnosis, were compared with AO-CRC (50 years and older). Patients with mismatch repair deficient tumors, CRC-related hereditary syndromes, and inflammatory bowel disease were excluded from all but the germline analysis. All statistical tests were 2-sided.
In total, 759 patients with EO-CRC (35 years, n = 151; 36-49 years, n = 608) and AO-CRC (n = 687) were included. Left-sided tumors (35 years and younger = 80.8%; 36-49 years = 83.7%; AO = 63.9%; P < .001 for both comparisons), rectal bleeding (35 years and younger = 41.1%; 36-49 years = 41.0%; AO = 25.9%; P = .001 and P < .001, respectively), and abdominal pain (35 years and younger = 37.1%; 36-49 years = 34.0%; AO = 26.8%; P = .01 and P = .005, respectively) were more common in EO-CRC. Among microsatellite stable tumors, we found no differences in histopathologic tumor characteristics. Initially, differences in TP53 and Receptor Tyrosine Kinase signaling pathway (RTK-RAS)alterations were noted by age. However, on multivariate analysis including somatic gene analysis and tumor sidedness, no statistically significant differences at the gene or pathway level were demonstrated. Among advanced microsatellite stable CRCs, chemotherapy response and survival were equivalent by age cohorts. Pathogenic germline variants were identified in 23.3% of patients 35 years and younger vs 14.1% of AO-CRC (P = .01).
EO-CRCs are more commonly left-sided and present with rectal bleeding and abdominal pain but are otherwise clinically and genomically indistinguishable from AO-CRCs. Aggressive treatment regimens based solely on the age at CRC diagnosis are not warranted.
Publication Date: 2021-08-19
Journal: Journal of the National Cancer Institute
[Exploring efficacy of Chinese medicine injection for promoting blood circulation and removing blood stasis in treatment of acute cerebral infarction based on two complex network analysis methods].
This study aims to explore the efficacy of Chinese medicine injections( CMIs) for promoting blood circulation and removing blood stasis for acute cerebral infarction from the perspectives of clinical medication and mechanism of action based on two complex network analysis methods. Firstly,the current 13 kinds of CMIs for acute cerebral infarction were obtained from 2019 List of medicines for national basic medical insurance,industrial injury insurance and maternity insurance with the method of network Meta-analysis. Secondly,with the use of network pharmacology,the mechanisms of top 2 CMIs with the highest therapeutic effect for acute cerebral infarction were explored from two levels including core target and network function enrichment. The result of network Meta-analysis showed Mailuoning Injection was superior to Danhong Injection in terms of total effectiveness rate for neurological deficit score and NIHSS score. The network pharmacology results showed that Mailuoning Injection had more core targets,interaction networks,enriched biological functions and more signaling pathways than Danhong Injection for cerebral infarction. Both two CMIs can play a role in treating cerebral infarction through core targets such as TP53 and NOS3,biological processes such as fibrinolysis,nitric oxide biosynthesis,nitric oxide-mediated signal transduction,negative regulation of apoptosis in endothelial cells and apoptosis process,as well as the signaling pathways such as PI3 K-Akt signaling pathway,HIF-1 signaling pathway and cell apoptosis signaling pathways. The results of pharmacological studies explained their differences in clinical efficacy to a certain extent. A research strategy based on curative effect should be advocated in efficacy evaluation of traditional Chinese medicine,where comparative research on clinical efficacy can be conducted firstly,and then mechanism research based on outstanding effective drugs to better provide references and basis for selection of similar competitive drugs for one disease in the clinical practice.
Publication Date: 2021-08-18
Journal: Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
Study on HOXBs of Clear Cell Renal Cell Carcinoma and Detection of New Molecular Target.
Our study examined the transcriptional and survival data of HOXBs in patients with clear cell renal cell carcinoma (ccRCC) from the ONCOMINE database, Human Protein Atlas, and STRING website. We discovered that the expression levels of HOXB3/5/6/8/9 were significantly lower in ccRCC than in normal nephritic tissues. In ccRCC, patients with a high expression of HOXB2/5/6/7/8/9 mRNA have a higher overall survival (OS) than patients with low expression. Further analysis by the GSCALite website revealed that the methylation of HOXB3/5/6/8 in ccRCC was significantly negatively correlated to gene expression, while HOXB5/9 was positively correlated to the CCT036477 drug target. As DNA abnormal methylation is one of the mechanisms of tumorigenesis, we hypothesized that HOXB5/6/8/9 are potential therapeutic targets for patients with ccRCC. We analyzed the function of enrichment data of HOXBs in patients with ccRCC from the Kyoto Encyclopedia of Genes and Genomes pathway enrichment and the PANTHER pathway. The results of the analysis show that the function of HOXBs might be associated with the Wnt pathway and that HOXB5/6/8/9 was coexpressed with multiple Wnt pathway classical genes and proteins, such as MYC, CTNNB, Cyclin D1 (CCND1), and tumor protein P53 (TP53), which further confirms that HOXBs inhibit the growth of renal carcinoma cells through the Wnt signaling pathway. In conclusion, our analysis of the family of HOXBs and their molecular mechanism may provide a theoretical basis for further research.
Publication Date: 2021-07-27
Journal: Journal of oncology
p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino.
Many long noncoding RNA (lncRNA) genes exist near cancer-associated loci, yet evidence connecting lncRNA functions to recurrent genetic alterations in cancer are lacking. Here, we report that DINO, the lncRNA transcribed from the cancer-associated DINO/CDKN1A locus, suppresses tumor formation independent of p21, the protein encoded at the locus. Loss of one or two alleles of Dino impairs p53 signaling and apoptosis, resulting in a haplo-insufficient tumor suppressor phenotype in genetically defined mouse models of tumorigenesis. A discrete region of the DINO/CDKN1A locus is recurrently hypermethylated in human cancers, silencing DINO but not CDKN1A, the gene encoding p21. Hypermethylation silences DINO, impairs p53 signaling pathway in trans, and is mutually exclusive with TP53 alterations, indicating that DINO and TP53 comprise a common tumor suppressor module. Therefore, DINO encodes a lncRNA essential for tumor suppression that is recurrently silenced in human cancers as a mechanism to escape p53-dependent tumor suppression.
Publication Date: 2021-07-01
Journal: Cell reports
Semen Cuscutae-Fructus Lycii improves spermatogenic dysfunction by repairing the blood-testis barrier in rats according to in silico and in vitro methods.
Semen Cuscutae and Fructus Lycii (SC-FL) is a commonly used herbal pair for male infertility treatment. Studies have found that the mechanism of SC-FL treatment may be related to repairing the blood-testis barrier (BTB). The application of network pharmacology can be used to explore the correlation between medicines and diseases and predict the potential pharmacological mechanisms of SC-FL.
This study aimed to explore the specific effects and mechanisms of SC-FL in repairing the BTB and initially revealed the mechanism of Chinese medicine treating male infertility through network pharmacology and animal experiments.
We searched databases using the network pharmacology method and performed mass spectrometry analysis. We analyzed and predicted the active ingredients, targets and key pathways of SC-FL in male infertility treatment. Then, we designed animal experiments to verify the results. Thirty-six Sprague-Dawley rats were randomly divided into the normal control group (NC group), spermatogenic dysfunction group (SD group) and SC-FL treatment group (SCFL group). Glucosides of Tripterygium wilfordii Hook. F (GTW) (40 mg/kg/d) was administered for 4 weeks to generate a spermatogenic dysfunction model. The rats in the SCFL group were given the SC-FL suspension (6 g/kg/d) daily. After 4 weeks of treatment, we detected the sperm quality of each group of rats and observed the cell morphology. Western blotting and qRT-PCR were used to detect the expression of BTB-related proteins in testicular tissues.
213 chemical ingredients of SC and FL were retrieved from the TCMSP database, and 54 effective chemical ingredients were obtained. Mass spectrometry analysis showed the above results were credible. Then, we identified 44 potential targets for the treatment of male infertility, and we plotted a network diagram of the interaction network between the core targets and a diagram of herbal medicine-active ingredient-target-disease interactions. The target genes were enriched according to biological functions, and 22 biological processes, 49 cellular components, 1487 molecular functions, and 122 signaling pathways were obtained. The results of the animal experiments showed that the sperm concentration and motility of the SCFL group were significantly improved compared with those of the SD group. Compared with those in the SD group, the structure and morphology of the Sertoli cells and seminiferous tubules of rats in the SCFL group improved, and the number of spermatogenic cells increased significantly. Western blotting and qRT-PCR results showed that compared with that in the SD group, the expression of p38 MAPK decreased significantly, and the expression of c-Jun, Occludin, ZO-1 and connexin 43 increased significantly in the SCFL group.
We predicted that the active ingredients of SC-FL can treat male infertility by interacting with the core targets JUN, IL6, MAPK1, TP53, MYC, CCND1, AR, EGF, FOS, and MAPK8, and the possible mechanism is related to the MAPK signaling pathway. SC-FL can regulate the MAPK pathway and affect the expression of Occludin, ZO-1 and connexin 43 to repair damaged BTB and improve spermatogenic dysfunction induced by GTW, which may be one of the possible mechanisms.
Publication Date: 2021-03-21
Journal: Journal of ethnopharmacology
Analysis of TP53 gene and particular infrastructural alterations in invasive ductal mammary carcinoma.
This study was conducted in order to determine the mutational status of TP53 gene and to determine some particular aspects from ultrastructural level in invasive mammary ductal carcinoma. The cellular signaling pathway involving the TP53 gene acts in biological deoxyribonucleic acid (DNA) repair processes and cell cycle arrest following a signal transmitted to the p53 protein when posttranslational changes occur in the cell due to stress induced in the cell by both intrinsic and extrinsic factors. Cellular stress activates the transcription factor function of the protein that initiates, as the case may be, either DNA repair or programmed cell death (apoptosis). The TP53 gene is commonly mutated in many human cancers and also has a highly polymorphic grade. To determine the mutational status of the exons 4-9 of the TP53 gene, we used extracted DNA from fresh breast tissue, and we analyzed it through direct sequencing. In mammary carcinoma, the mutation frequency of TP53 is running between 20-40% and, in regards the polymorphism, at least 14 different forms were identified, that are associated with cancer risk. The mutation type distribution showed a predominance of deletions and a reduced frequency of substitutions comparing with International Agency for Research on Cancer (IARC) database. Taken in consideration the importance of the tumor associated stroma in tumor development, we have also investigated some particular aspects at the infrastructural level of invasive mammary ductal carcinoma, notably concerning telocytes as tumor stroma interstitial cells by transmission electron microscopy analysis.
Publication Date: 2021-02-06
Journal: Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie
[Potential molecular mechanism of Banxia Xiexin Decoction in treatment of colon cancer based on network pharmacology and molecular docking technology].
The aim of this paper was to explore the potential molecular mechanism of Banxia Xiexin Decoction in the treatment of colon cancer through pharmacology network and molecular docking methods. The chemical constituents and action targets of 7 herbs from Banxia Xiexin Decoction were collected by using TCMSP database,Chinese Pharmacopoeia and literatures consultation. GeneCards database was used to predict the potential targets of colon cancer. GO biological process analysis and KEGG pathway enrichment analysis of the disease and drug intersection targets were carried out through DAVID database. "Component-target-pathway" network and protein-protein interaction(PPI) network were construction by using Cytoscape and STRING database,and then the core components and targets of Banxia Xiexin Decoction in the treatment of colon cancer were selected according to the topological parameters. Finally, Autodock Vina was used to realize the molecular docking of core components and key targets. The prediction results showed that there were 190 active compounds and 324 corresponding targets for Banxia Xiexin Decoction,involving 74 potential targets for colon cancer. Cytoscape topology analysis revealed 11 key targets such as STAT3,TP53,AKT1,TNF,IL6 and SRC, as well as 10 core components such as quercetin,β-sitosterol,baicalein,berberine,and 6-gingerol.In bioinformatics enrichment analysis, 679 GO terms and 106 KEGG pathways were obtained, mainly involving PI3 K-AKT signaling pathway,TNF signaling pathway and TP53 signaling pathway. The results of molecular docking showed that baicalein,berberine,licochalcone A and 6-gingerol had a high affinity with SRC,STAT3,TNF and IL6. The results suggested that Banxia Xiexin Decoction could play an anti-colon cancer effect by inhibiting cell proliferation, regulating cell cycle, inducing apoptosis and anti-inflammatory function. The study revealed the multi-components,multi-targets and multi-pathways molecular mechanism of Banxia Xiexin Decoction,which could provide scientific basis and research ideas for the clinical application of Banxia Xiexin Decoction and the treatment of colon cancer with compound Chinese medicines.
Publication Date: 2021-01-27
Journal: Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
Mechanism of miR-122-5p regulating the activation of PI3K-Akt-mTOR signaling pathway on the cell proliferation and apoptosis of osteosarcoma cells through targeting TP53 gene.
To explore the regulatory mechanism of microRNA-122-5p (miR-122-5) targeting tumor protein p53 (TP53) gene to mediate PI3K-Akt-mTOR signaling pathway on the proliferation and apoptosis of osteosarcoma (OS) cells.
With the collection of osteosarcoma and normal adjacent tissues, the mRNA of miR-122-5p, TP53, PTEN, PI3K, Akt, mTOR, Bim, Bax, and Bcl-2 was detected by Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR), followed by the detection of the protein expression by Western blot. The target relationship between miR-122-5p and TP53 gene was verified. The third generation osteosarcoma cells were divided into Blank group, miR-122-5p mimic negative control (NC) group, miR-122-5p mimic group, miR-122-5p inhibitor NC group, miR-122-5p inhibitor group, rapamycin group and miR-122-5p inhibitor + rapamycin group. Furthermore, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry were used to detect the proliferation ability, cell cycle distribution and apoptosis of each group after transfection.
The expression level of miR-122-5p in osteosarcoma was lower than that in normal tissues (p < 0.05), TP53, PTEN, Bim and Bax expression levels were decreased (all p < 0.05), while the expression levels of PI3K, p-PI3K, Akt, p-Akt, mTOR, p-mTOR and Bcl-2 were highly upregulated (all p < 0.05). TP53 had the lowest expression in osteosarcoma cell line U-2OS (p < 0.05), which was selected for subsequent cell experiments. TP53 was the target gene of miR-122-5p. Compared with Blank group, miR-122-5p mimic group had increased expression of miR-122-5p (all p < 0.05); besides, there were significantly increased expression of TP53, PTEN, Bim, and Bax in miR-122-5p mimic group and rapamycin group, while remarkably decreased expression of PI3K, p-PI3K, Akt, p-Akt, mTOR, p-mTOR, and Bcl-2 (all p < 0.05), accompanied by increased proportion of cells in G0/G1 phase, decreased cell proportion in S phase, increased cell apoptosis and inhibited cell proliferation (all p < 0.05). The opposite trends were found in miR-122-5p inhibitor group relative to miR-122-5p mimic group and rapamycin group (all p < 0.05). Meanwhile, no significant difference was found in miR-122-5p inhibitor+rapamycin group when compared with that in Blank group (all p > 0.05) except for significantly decreased miR-122-5p expression (p < 0.05).
Upregulation of miR-122-5p may inhibit the proliferation and promote the apoptosis of osteosarcoma cells by inhibiting the activation of PI3K-Akt-mTOR signaling pathway, which may be related to the targeted up-regulation of TP53 expression.
Publication Date: 2020-12-31
Journal: European review for medical and pharmacological sciences
TP53 alterations of hormone-naïve prostate cancer in the Chinese population.
Prostate cancer (PCa) shows racial disparity in clinical and genomic characteristics, and Asian patients with PCa often present with more aggressive phenotypes at diagnosis. The ability of TP53 to serve as a prognostic biomarker of PCa has been well studied in Western populations. However, no studies to date have examined the role of TP53 in the disparities of primary hormone-naïve prostate cancer (HNPC) between Chinese and Western populations.
We collected prostate tumors and matched normal tissues or blood samples to perform targeted next-generation sequencing of 94 Chinese primary localized HNPC samples, and correlated these genomic profiles with clinical outcomes. The OncoKB knowledge database was used to identify and classify actionable alterations.
The aberrations of PTEN, CDK12, and SPOP in Chinese HNPC samples were similar to those in the Western samples. However, we demonstrated an association of a high frequency of TP53 alterations (21/94) with a relatively higher percentage of alterations in the Wnt signaling pathway (15/94) in Chinese HNPC. Additionally, we highlighted alterations of LRP1B as accounting for a high proportion of PCa and found more frequent alterations in CDH1 in Chinese PCa. Of these, only CDH1 alteration was associated with rapid biochemical recurrence (BCR). However, we verified that TP53 status was at the core of the genomic alteration landscape in Chinese HNPC with putative driver mutations because of the strong connections with other signaling pathways. The mutually exclusive relationship between alterations in TP53 and Wnt/CTNNB1 further molecularly characterizes subsets of prostate cancers. Moreover, the alteration of KMT2C was more likely to co-occur with TP53 alteration, indicating a more aggressive phenotype of PCa, which was associated with sensitivity to treatment with poly ADT-ribose polymerase (PARP) inhibitors.
Detection of TP53 alterations has clinical utility for guiding precision cancer therapy for HNPC, especially in the Chinese population.
Publication Date: 2020-11-21
Journal: Prostate cancer and prostatic diseases
Comprehensive bioinformatics analysis of the TP53 signaling pathway in Wilms' tumor.
Differential expression of tumor protein 53 (TP53, or p53) has been observed in multiple cancers. However, the expression levels and prognostic role of TP53 signaling pathway genes in Wilms' tumor (WT) have yet to be fully explored.
The expression levels of TP53 signaling pathway genes including TP53, mouse double minute 2 (MDM2), mouse double minute 4 (MDM4), cyclin-dependent kinase 2A (CDKN2A), cyclin-dependent kinase 2B (CDKN2B), and tumor suppressor p53-binding protein 1 (TP53BP1) in WT were analyzed using the Oncomine database. Aberration types, co-mutations, mutation locations, signaling pathways, and the prognostic role of TP53 in WT were investigated using cBioPortal. MicroRNA (miRNA) and transcription factor (TF) targets were identified with miRTarBase, miWalk, and ChIP-X Enrichment Analysis 3 (CheA3), respectively. A protein-protein network was constructed using GeneMANIA. The expression of TP53 signaling genes were confirmed in WT samples and normal kidney tissues using the Human Protein Atlas (HPA). Cancer Therapeutics Response Portal (CTRP) was used to analyze the small molecules potentially targeting TP53.
TP53 was significantly expressed in the Cutcliffe Renal (P=0.010), but not in the Yusenko Renal (P=0.094). Meanwhile, MDM2 was significantly overexpressed in the Yusenko Renal (P=0.058), but not in the Cutcliffe Renal (P=0.058). The expression levels of MDM4 no significant difference between the tumor and normal tissue samples. The most common TP53 alteration was missense and the proportion of TP53 pathway-related mutations was 2.3%. Co-expressed genes included ZNF609 (zinc finger protein 609), WRAP53 (WD40-encoding RNA antisense to p53), CNOT2 (CC chemokine receptor 4-negative regulator of transcription 2), and CDH13 (cadherin 13). TP53 alterations indicated poor prognosis of WT (P=1.051e-4). The regulators of the TP53 pathway included miR-485-5p and TFs NR2F2 and KDM5B. The functions of TP53 signaling pathway were signal transduction in response to DNA damage and regulate the cell cycle. The small molecules targeting TP53 included PRIMA-1, RITA, SJ-172550, and SCH-529074.
TP53 was found to be differentially expressed in WT tissues. TP53 mutations indicated poor outcomes of WT. Therefore, pifithrin-mu, PRIMA-1, RITA, SJ-172550, and SCH-529074 could be used in combination with traditional chemotherapy to treat WT.
Publication Date: 2020-11-13
Journal: Annals of translational medicine
Extracellular vesicles enriched with miR-150 released by macrophages regulates the TP53-IGF-1 axis to alleviate myocardial infarction.
Myocardial infarction (MI) is recognized as a major cause of death and disability around the world. Macrophage-derived extracellular vesicles (EVs) have been reportedly involved in the regulation of cellular responses to MI. Thus, we sought to clarify the mechanism by which macrophage-derived EVs regulate this process. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed to determine microRNA-150 (miR-150) expression in an MI mouse model with ligation of the left anterior descending coronary artery (LAD) and in hypoxia/reoxygenation (H/R)-exposed cardiomyocytes. Bioinformatics analysis and dual luciferase reporter gene assay were adopted to identify the correlation of miR-150 with tumor protein 53 (TP53) expression in cardiomyocytes. Gain- and loss-of-function experiments were conducted in H/R-induced cardiomyocytes, cardiomyocytes incubated with EVs from miR-150 mimic-transfected macrophages, or MI-model mice treated with EVs from miR-150 mimic-transfected macrophages. hematoxylin-eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining assays were used for detecting inflammatory infiltration and cell apoptosis. The release of lactate dehydrogenase (LDH) by dead cardiomyocytes was measured with an LDH kit, and the apoptosis-related proteins, Bax, and cleaved-caspase 3 were determined by Western blot analysis. miR-150 expression was downregulated in the infarcted cardiac tissues of MI mice. Macrophage-derived EVs could transfer miR-150 into cardiomyocytes, where it directly targeted and suppressed TP53. Furthermore, miR-150 suppressed phosphatase and tensin homology (PTEN) and activated p-Akt to upregulate IGF-1 expression. Furthermore, increased expression of EV-derived miR-150 prevented cardiomyocyte apoptosis in vitro, as evidenced by downregulated Bax and cleaved-caspase 3 and upregulated Bcl2 and alleviated MI in vivo. In conclusion, our study demonstrates the cardioprotective effect of macrophage-derived EV-miR-150 on MI-induced heart injury through negatively regulating the TP53-IGF-1 signaling pathway.
Publication Date: 2020-11-10
Journal: American journal of physiology. Heart and circulatory physiology
Mutational landscape of gray zone lymphoma.
The mutational landscape of gray zone lymphoma (GZL) has not yet been established, and differences from related entities are largely unknown. Here, we studied coding sequence mutations of 50 Epstein-Barr virus (EBV)-negative GZLs and 20 polymorphic EBV+ diffuse large B-cell lymphoma (DLBCL) not otherwise specified (poly-EBV-L) in comparison with classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), and DLBCL. Exomes of 21 GZL and 7 poly-EBV-L cases, along with paired constitutional DNA, were analyzed as a discovery cohort, followed by targeted sequencing of 217 genes in an extension cohort of 29 GZL and 13 poly-EBV-L cases. GZL cases with thymic niche involvement (anterior mediastinal mass) exhibited a mutation profile closely resembling cHL and PMBCL, with SOCS1 (45%), B2M (45%), TNFAIP3 (35%), GNA13 (35%), LRRN3 (32%), and NFKBIA (29%) being the most recurrently mutated genes. In contrast, GZL cases without thymic niche involvement (n = 18) had a significantly distinct pattern that was enriched in mutations related to apoptosis defects (TP53 [39%], BCL2 [28%], BIRC6 [22%]) and depleted in GNA13, XPO1, or NF-κB signaling pathway mutations (TNFAIP3, NFKBIE, IKBKB, NFKBIA). They also exhibited more BCL2/BCL6 rearrangements compared with thymic GZL. Poly-EBV-L cases presented a distinct mutational profile, including STAT3 mutations and a significantly lower coding mutation load in comparison with EBV- GZL. Our study highlights characteristic mutational patterns in GZL associated with presentation in the thymic niche, suggesting a common cell of origin and disease evolution overlapping with related anterior mediastinal lymphomas.
Publication Date: 2020-09-23
Interplay between HMGA and TP53 in cell cycle control along tumor progression.
The high mobility group A (HMGA) proteins are found to be aberrantly expressed in several tumors. Studies (in vitro and in vivo) have shown that HMGA protein overexpression has a causative role in carcinogenesis process. HMGA proteins regulate cell cycle progression through distinct mechanisms which strongly influence its normal dynamics along malignant transformation. Tumor protein p53 (TP53) is the most frequently altered gene in cancer. The loss of its activity is recognized as the fall of a barrier that enables neoplastic transformation. Among the different functions, TP53 signaling pathway is tightly involved in control of cell cycle, with cell cycle arrest being the main biological outcome observed upon p53 activation, which prevents accumulation of damaged DNA, as well as genomic instability. Therefore, the interaction and opposing effects of HMGA and p53 proteins on regulation of cell cycle in normal and tumor cells are discussed in this review. HMGA proteins and p53 may reciprocally regulate the expression and/or activity of each other, leading to the counteraction of their regulation mechanisms at different stages of the cell cycle. The existence of a functional crosstalk between these proteins in the control of cell cycle could open the possibility of targeting HMGA and p53 in combination with other therapeutic strategies, particularly those that target cell cycle regulation, to improve the management and prognosis of cancer patients.
Publication Date: 2020-09-14
Journal: Cellular and molecular life sciences : CMLS
A Network Pharmacology Approach to Reveal the Underlying Mechanisms of Zuogui Yin in the Treatment of Male Infertility.
Traditional Chinese medicine (TCM), as a complementary and alternative therapy, has played increasingly important roles in clinical treatment and disease prevention. Zuogui Yin (ZGY) is one of the well-known TCM prescriptions used for the treatment of male infertility. To fully reveal the potential mechanisms underlying the therapeutic effects of ZGY on male infertility, a network pharmacology approach was conducted at the molecular level.
Network pharmacology approach was used in this study, which mainly included active compound screening, target prediction, gene enrichment analysis, and network analysis.
The network analysis successfully identified 148 potential active ingredients of ZGY and 155 predicted targets that were associated with male infertility. ZGY might play a role in the treatment of male infertility by regulating ten hub targets (VEGFA, CASP3, TNF, AKT1, EGF, EGFR, IL-6, MAPK1, TP53, and PTGS2) and six pathways (TNF signaling pathway, PI3K-Akt signaling pathway, FoxO signaling pathway, Toll-like receptor signaling pathway, VEGF signaling pathway, and MAPK signaling pathway).
This study explored the pharmacological activity and molecular mechanisms of ZGY against male infertility from a holistic perspective. The underlying molecular mechanisms were closely related to the intervention of oxidative stress and apoptosis with CASP3, TP53, AKT1, and MAPK1 being possible targets.
Publication Date: 2020-08-26
Journal: Combinatorial chemistry & high throughput screening
The Tumor Suppressive Roles and Prognostic Values of STEAP Family Members in Breast Cancer.
To investigate the expression patterns and prognostic values of STEAP family members in the occurrence and development of breast cancer.
The Human Protein Atlas was used to analyze the expression level of STEAPs in human normal tissues and malignant tumors. ONCOMINE datasets were analyzed for the comparison of the STEAPs levels between malignant cancers and corresponding normal tissues. Kaplan-Meier plotter was used to analyze the prognostic value of STEAPs in breast cancer patients.
STEAPs were widely distributed in human normal tissues with diverse levels. Normally, it is predicted that STEAP1 and STEAP2 were involved in the mineral absorption process, while STEAP3 participated in the TP53 signaling pathway and iron apoptosis. The results from ONCOMINE showed downregulation of STEAP1, STEAP2, and STEAP4 in breast cancers. Survival analysis revealed that breast cancer patients with high levels of STEAP1, STEAP2, and STEAP4 had a good prognosis, while those with low expression had high overall mortality.
STEAP1, STEAP2, and STEAP4 are predicted to be the potential prognostic biomarkers for breast cancer patients, providing novel therapeutic strategies for them.
Publication Date: 2020-08-18
Journal: BioMed research international
Chronic lymphocytic leukemia (CLL) risk is mediated by multiple enhancer variants within CLL risk loci.
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. It has a strong genetic basis, showing a ~ 8-fold increased risk of CLL in first-degree relatives. Genome-wide association studies (GWAS) have identified 41 risk variants across 41 loci. However, for a majority of the loci, the functional variants and the mechanisms underlying their causal roles remain undefined. Here, we examined the genetic and epigenetic features associated with 12 index variants, along with any correlated (r2 ≥ 0.5) variants, at the CLL risk loci located outside of gene promoters. Based on publicly available ChIP-seq and chromatin accessibility data as well as our own ChIP-seq data from CLL patients, we identified six candidate functional variants at six loci and at least two candidate functional variants at each of the remaining six loci. The functional variants are predominantly located within enhancers or super-enhancers, including bi-directionally transcribed enhancers, which are often restricted to immune cell types. Furthermore, we found that, at 78% of the functional variants, the alternative alleles altered the transcription factor binding motifs or histone modifications, indicating the involvement of these variants in the change of local chromatin state. Finally, the enhancers carrying functional variants physically interacted with genes enriched in the type I interferon signaling pathway, apoptosis, or TP53 network that are known to play key roles in CLL. These results support the regulatory roles for inherited noncoding variants in the pathogenesis of CLL.
Publication Date: 2020-08-04
Journal: Human molecular genetics
A Network Pharmacology Approach to Investigate the Active Compounds and Mechanisms of Musk for Ischemic Stroke.
This study aims to study the material basis and effective mechanism of musk for ischemic stroke (IS) based on the network pharmacology approach.
We collected the chemical components and target gene of musk from the BATMAN-TCM analytical platform and identified ischemic stroke-related targets from the following databases: DisGeNET, NCBI-Gene, HPO, OMIM, DrugBank, and TTD. The targets of musk and IS were uploaded to the String database to construct the protein-protein interaction (PPI) network, and then, the key targets were analyzed by topological methods. At last, the function biological process and signaling pathways of key targets were carried out by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and cluster analysis by using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server and Metascape platform.
A total of 29 active compounds involving 1081 predicted targets were identified in musk and there were 1104 IS-related targets. And 88 key targets of musk for IS were obtained including AKT1, MAPK1/3, TP53, TNF, SRC, FOS, CASP3, JUN, NOS3, and IL1B. The GO and KEGG enrichment analysis suggested that these key targets are mainly involved in multiple pathways which participated in TNF signaling pathway, estrogen signaling pathway, prolactin signaling pathway, neurotrophin signaling pathway, T-cell receptor signaling pathway, cAMP signaling pathway, FoxO signaling pathway, and HIF1 signaling pathway.
This study revealed that the effective mechanisms of musk against IS would be associated with the regulation of apoptosis, inflammatory response, and gene transcription.
Publication Date: 2020-07-28
Journal: Evidence-based complementary and alternative medicine : eCAM
Expression Patterns of Immune Genes Reveal Heterogeneous Subtypes of High-Risk Neuroblastoma.
High risk neuroblastoma (HR-NB) remains difficult to treat, and its overall survival (OS) is still below 50%. Although HR-NB is a heterogeneous disease, HR-NB patients are currently treated in a similar fashion. Through unsupervised biclustering, we further stratified HR-NB patients into two reproducible and clinically distinct subtypes, including an ultra-high risk neuroblastoma (UHR-NB) and high risk neuroblastoma (HR-NB). The UHR-NB subtype consistently had the worst OS in multiple independent cohorts ( P < 0 . 008 ). Out of 283 neuroblastoma-specific immune genes that were used for stratification, 39 of them were differentiated in UHR-NB, including four upregulated and 35 downregulated, as compared to HR-NB. The four UHR-NB upregulated genes (ADAM22, GAL, KLHL13 and TWIST1) were all upregulated in MYCN amplified neuroblastoma in 5 additional cohorts. TWIST1 and ADAM22 were also positively correlated with cancer stage, while GAL was an independent OS predictor in addition to MYCN and age. Furthermore, we identified 26 commonly upregulated and 311 downregulated genes in UHR-NB from all 4723 immune-related genes. While 43 KEGG pathways with molecular functions were enriched in the downregulated immune-related genes, only the P53 signaling pathway was enriched in the upregulated ones, which suggested that UHR-NB was a TP53 related subtype with reduced immune activities.
Publication Date: 2020-07-08