Proto-oncogene Protein Research Articles

Condensate remodeling reorganizes innate SS18 in synovial sarcomagenesis

SS18-SSX onco-fusion protein formed through aberrant chromosomal translocation t (X, 18; p11, q11), is the hallmark and plays a critical role in synovial sarcomagenesis. The recent works indicated that both the pathological SS18-SSX tumorigenic fusion and the corresponding intrinsic physiological SS18 protein can form condensates but appear to have disparate properties. The underlying regulatory mechanism and the consequent biological significance remain largely unknown. We show that the physical properties of oncogenic fusion protein SS18-SSX condensates within cells undergo alterations compared to the proto-oncogene protein SS18. By small-molecule screening and mutant assay, we identified the recognition of H2AK119ub histone modification could account for the distinctive properties of SS18-SSX1 condensates. Notably, we show that SS18-SSX1 condensates have impact on SS18 condensates and hijack that in a phase separation manner, resulting in the relocation of protein SS18 to the H2AK119ub modification targeted by SS18-SSX1. Consequently, this leads to the downregulation of tumor suppressor genes occupied by SS18 physiologically, like CAV1 and DAB2. These results reveal the underlying mechanism of genomic disorder and tumorigenesis caused by the remodeling of oncoprotein SS18-SSX1 condensates at the macroscopic level.

Phosphorylation-induced flexibility of proto-oncogenic Bcl3 regulates transcriptional activation by NF-κB p52 homodimer.

B cell lymphoma 3 (Bcl3), a member of the IκB family proteins, modulates transcription by primarily associating with NF-κB p50 and p52 homodimers. Bcl3 undergoes extensive phosphorylation, though the functions of many of these modifications remain unclear. We previously described that phosphorylation at Ser33, Ser114 and Ser446 partially switches Bcl3 from acting as an IκB-like inhibitor to a transcription regulator by associating with the (p52:p52):DNA binary complex. Here, we identified another critical phosphorylation site, Ser366. Substituting at all four residues to phospho-mimetic glutamate further enhances Bcl3's transcriptional activity. Phospho-modifications retain Bcl3's ability to stably bind p52 but induces reciprocal structural changes as revealed by HDX-MS experiments; the N-terminal region stiffens, while the C-terminus becomes more flexible. The increased flexibility allowed the Bcl3:(p52p52) binary complex to better accommodate DNA. The removal of the C-terminal 28-residues transformed Bcl3 into a transcriptional activator independent of phosphorylation. Notably, most identified mutations in Bcl3 from various cancers map to its C-terminus, suggesting the functional relevance of Bcl3 C-terminal structural flexibility and enhanced interaction with (p52p52):DNA complex to transcriptional potential and disease. Overall, this study uncovers the mechanistic basis by which phosphorylation-driven structural changes convert Bcl3 from an inhibitor to a transcriptional cofactor of NF-κB, and how deregulation of its activity through altered phosphorylation or mutation can lead to cancer.

Heightened TPD52 linked to metabolic dysfunction and associated abnormalities in zebrafish

The tumor protein D52 (TPD52) gene encodes a proto-oncogene protein associated with various medical conditions, including breast and prostate cancers. It plays a role in multiple biological pathways such as cell growth, differentiation, and apoptosis. The function of TPD52 in lipid droplet biosynthesis has been investigated in vitro. However, its precise role in lipid metabolism in animal models is not fully understood. To investigate the functions of TPD52 in vivo, we performed a conditional TPD52 protein expression analysis using a Tet-off transgenic system to establish conditionally expressed Tpd52 transgenic zebrafish. The effect of Tpd52 on lipogenesis was assessed using various methods, including whole-mount Oil Red O staining, histological examination, and measurement of inflammatory markers and potential targets using real-time quantitative polymerase chain reaction and immunoblotting in Tpd52 fish. Zebrafish with increased Tpd52 levels exhibited notable weight gain and the enlargement of fat deposits, which were mainly attributed to an increase in the volume of adipocytes. Moreover, Tpd52 overexpression was correlated with the triggering of the adipocyte differentiation signaling pathway. During adipocytic differentiation in response to nutrient status, our observations revealed adipogenesis, nonalcoholic fatty liver disease, and metabolic cardiomyopathy (MCM) in Tpd52 transgenic zebrafish. To gain a deeper understanding of the contribution of these proteins to the regulation of cellular growth, we investigated the expression of their corresponding genes and proteins in zebrafish. In the present study, the activated protein kinase pathway was identified as the primary target of TPD52. Adult Tpd52 zebrafish showed increased lipid accumulation, resulting in the development of visceral obesity, nonalcoholic fatty liver disease, and MCM. These findings strongly suggest that TPD52 actively contributes to adipose tissue expansion and its subsequent effects. This investigation provides compelling evidence that Tpd52 facilitates adipocyte development and related metabolic comorbidities in zebrafish.

Transcription factor 4 is a key mediator of oncogenesis in neuroblastoma by promoting MYC activity.

Super-enhancer-associated transcription factor networks define cell identity in neuroblastoma (NB). Dysregulation of these transcription factors contributes to the initiation and maintenance of NB by enforcing early developmental identity states. We report that the class I basic helix-loop-helix (bHLH) transcription factor 4 (TCF4; also known as E2-2) is a critical NB dependency gene that significantly contributes to these identity states through heterodimerization with cell-identity-specific bHLH transcription factors. Knockdown of TCF4 significantly induces apoptosis in vitro and inhibits tumorigenicity in vivo. We used genome-wide expression profiling, TCF4 chromatin immunoprecipitation sequencing (ChIP-seq) and TCF4 immunoprecipitation-mass spectrometry to determine the role of TCF4 in NB cells. Our results, along with recent findings in NB for the transcription factors T-box transcription factor TBX2, heart- and neural crest derivatives-expressed protein 2 (HAND2) and twist-related protein 1 (TWIST1), propose a role for TCF4 in regulating forkhead box protein M1 (FOXM1)/transcription factor E2F-driven gene regulatory networks that control cell cycle progression in cooperation with N-myc proto-oncogene protein (MYCN), TBX2, and the TCF4 dimerization partners HAND2 and TWIST1. Collectively, we showed that TCF4 promotes cell proliferation through direct transcriptional regulation of the c-MYC/MYCN oncogenic program that drives high-risk NB. Mechanistically, our data suggest the novel finding that TCF4 acts to support MYC activity by recruiting multiple factors known to regulate MYC function to sites of colocalization between critical NB transcription factors, TCF4 and MYC oncoproteins. Many of the TCF4-recruited factors are druggable, giving insight into potential therapies for high-risk NB. This study identifies a new function for class I bHLH transcription factors (e.g., TCF3, TCF4, and TCF12) that are important in cancer and development.

Genetic Analysis of Potential Biomarkers and Therapeutic Targets in Ferroptosis from Steroid-Induced Osteonecrosis of the Femoral Head Based on Machine Learning.

To locate the candidate therapeutic target genes involved in ferroptosis in steroid-induced osteonecrosis of the femoral head (SONFH). Bioinformatics analysis study. Place and Duration of the Study: Department of Orthopaedic Surgery, Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, Guangdong, China, from March to July 2023. After processing the gene expression omnibus (GEO) data with the R programming language, differentially expressed ferroptosis-related genes in SONFH were identified. To pinpoint the genes most strongly linked to SONFH in association with ferroptosis, least absolute shrinkage and selection operator (LASSO) regression and support vector machine-recursive feature elimination (SVM-RFE) were employed. Subsequently, the screened essential genes were analysed to investigate immune cell infiltration, and competing endogenous RNA (ceRNA) networks involving these marker genes were constructed. The machine learning algorithms identified three genes i.e., SOCS1 (suppressor of cytokine signalling1), MYCN (N-myc proto-oncogene protein), and KLF2 (Kruppel-like factor 2) as diagnostic feature biomarkers associated with ferroptosis. Additionally, CIBERSORT analysis revealed that alterations in the immune microenvironment, such as Macrophages M1, Monocytes, and T cells CD4 naive, could be linked to SOCS1, MYCN, and KLF2. Moreover, the competing endogenous RNA (ceRNA) network exposed a complex regulatory relationship based on marker genes. SOCS1, MYCN, and KLF2 are potential biomarkers associated with ferroptosis in SONFH, pending confirmation in future studies. Steroid-induced osteonecrosis of the femoral head, Ferroptosis, Machine learning, Genetic analysis.

A Study Against Colon Cancer Mechanism of Xanthium sibiricum Herba Based on Computer Simulation and Bioinformatics.

Cancer is one of the leading causes of death worldwide, accounting for nearly one in six deaths in 2020. As a folk medicine, Xanthium sibiricum Herba (XSH) has been used many times in clinical practice for the treatment of various diseases. With the increasing number of cancer patients, there is a clinical need to find effective anti-cancer drugs. This study aims to explores the bioactivity and the anti-cancer mechanism of XSH. In this study, bioinformatics, network pharmacology, molecular docking, molecular dynamics simulation techniques, and apoptosis assay were used to explore the bioactivity and the anti- cancer mechanism of XSH. Finally, seven active ingredients in XSH after the screening were obtained, the two most active compounds were β-sitosterol and aloe-emodin, and good anti-cancer activity of XSH was predicted. Four core targets were obtained from the PPI network map, namely Caspase-3 (CASP3), Transcription factor AP-1 (JUN), Myc proto-oncogene protein (MYC), and cellular tumor antigen p53 (TP53). GO and KEGG analyses showed that the mechanism of XSH anti-cancer is mainly related to the apoptosis process, and the main signaling pathways are enriched in the p53 signaling pathway, Apoptosis, and MAPK signaling. The molecular docking and molecular dynamics simulation results showed that CASP3, JUN, MYC, and TP53 had a high affinity with β- sitosterol and aloe-emodin. Bioinformatics analyses demonstrated the importance of core targets. Apoptosis assay showed that XSH could significantly promote the apoptosis of cancer cells, and inhibit their proliferation and migration, especially colon cancer cells. This study uncovered the main active components, bioactivities, and potential targets of XSH, and further revealed the multi-component, multi-target, and multi-pathway mechanism of XSH for cancer treatment and promoting apoptosis.

Combination of high anti-SKI and low anti-TMED5 antibody levels is preferable prognostic factor in esophageal carcinoma.

Given that esophageal cancer is highly malignant, the discovery of novel prognostic markers is eagerly awaited. We performed serological identification of antigens by recombinant cDNA expression cloning (SEREX) and identified SKI proto-oncogene protein and transmembrane p24 trafficking protein 5 (TMED5) as antigens recognized by serum IgG antibodies in patients with esophageal carcinoma. SKI and TMED5 proteins were expressed in Escherichia coli, purified by affinity chromatography, and used as antigens. The serum anti-SKI antibody (s-SKI-Ab) and anti-TMED5 antibody (s-TMED5-Ab) levels were significantly higher in 192 patients with esophageal carcinoma than in 96 healthy donors. The presence of s-SKI-Abs and s-TMED5-Abs in the patients' sera was confirmed by western blotting. Immunohistochemical staining showed that the TMED5 protein was highly expressed in the cytoplasm and nuclear compartments of the esophageal squamous cell carcinoma tissues, whereas the SKI protein was localized predominantly in the nuclei. Regarding the overall survival in 91 patients who underwent radical surgery, the s-SKI-Ab-positive and s-TMED5-Ab-negative statuses were significantly associated with a favorable prognosis. Additionally, the combination of s-SKI-Ab-positive and s-TMED5-Ab-negative cases showed an even clearer difference in overall survival as compared with that of s-SKI-Ab-negative and s-TMED5-Ab-positive cases. The s-SKI-Ab and s-TMED5-Ab biomarkers are useful for diagnosing esophageal carcinoma and distinguishing between favorable and poor prognoses.

Mocetinostat as a Novel Selective Histone Deacetylase Inhibitor in the Promotion of Apoptosis in glioblastoma Cell Line C6 and T98G

Abstract Background: Histone deacetylase (HDAC) enzymes play a crucial role in regulating gene expression and epigenetic alterations in cancer cells. Mocetinostat (MGCD0103) is a novel, isotype-selective HDAC inhibitor that targets Class I (HDAC1, 2, 3, and 8) and Class IV (HDAC11) enzymes. It has been approved for the use in phase II trials for Hodgkin’s lymphoma. Methods: In this study, the glioblastoma cell (GBM) lines T98G and C6 were treated with different concentrations of MGCD0103 (0.0, 0.5, 1.0, 1.5, 2.0, and 2.5 μM). Western blot analysis was used to evaluate protein expression and flow cytometry was employed to assess apoptosis. Results: The results demonstrated that MGCD0103 exerts multiple anti-cancer activities in GBMs. MGCD0103 modulated key signaling pathways, including inhibition of the Phosphatidylinositol 3- kinase (PI3K)/protein kinase B mechanism pathway and suppression of HDAC1 enzyme activity. High doses of MGCD0103 significantly induced apoptosis and suppressed cell proliferation by upregulating the pro-apoptotic protein Bcl-2-associated protein x and downregulating the anti-apoptotic proteins BH3 Interacting Domain Death Agonist and B-cell leukemia/lymphoma 2 protein. In addition, MGCD0103 treatment upregulated the expression of the tumor-suppressor gene and downregulated the E2F1 transcription factor. Furthermore, MGCD0103 facilitated cell differentiation by activating the glial fibrillary acidic protein Glial Fibrillary acidic protein (GFAP) as distinguish marker of astrocytes, and suppressing the undifferentiation markers Inhibitor of Deoxyribonucleic acid binding 2 and N-Myc proto-oncogene protein. Conclusion: This research suggests that MGCD0103 is a promising drug for inhibiting the proliferation, invasion, and migration of GBMs. The findings also provide new insights into the ability of MGCD0103 to induce differentiation in GBMs. Overall, these results indicate that MGCD0103 could be a potent therapeutic agent for the target of glioblastoma.

Impact of RAAS Receptors and Membrane-Bound Transporter System in the Left Ventricle during the Long-Term Control of Hypertension.

The Renin-Angiotensin-Aldosterone System (RAAS) has been implicated in systemic and neurogenic hypertension. The infusion of RAAS inhibitors blunted arterial pressure and efficacy of use-dependent synaptic transmission in sympathetic ganglia. The current investigation aims to elucidate the impact of RAAS-mediated receptors on left ventricular cardiomyocytes and the role of the sarcolemma-bound carrier system in the heart of the hypertensive transgene model. A significant increase in mRNA and the protein expression for angiotensin II (AngII) receptor subtype-1 (AT1R) was observed in (mREN2)27 transgenic compared to the normotensive rodents. Concurrently, there was an upregulation in AT1R and a downregulation in the MAS1 proto-oncogene protein receptor as well as the AngII subtype-2 receptor in hypertensive rodents. There were modifications in the expressions of sarcolemma Na+-K+-ATPase, Na+-Ca2+ exchanger, and Sarcoendoplasmic Reticulum Calcium ATPase in the transgenic hypertensive model. These observations suggest chronic RAAS activation led to a shift in receptor balance favoring augmented cardiac contractility and disruption in calcium handling through modifications of membrane-bound carrier proteins and blood pressure. The study provides insight into mechanisms underlying RAAS-mediated cardiac dysfunction and highlights the potential value of targeting the protective arm of AngII in hypertension.

Anti-inflammatory effect and its mechanism of Saracae Cortex based on zebrafish model and network pharmacology

This paper aims to explore the anti-inflammatory mechanism of Saracae Cortex by using network pharmacology and molecular docking methods and verify it through the inflammation model of zebrafish. The effective components, potential core targets, and signaling pathways of Saracae Cortex were obtained by using network pharmacology. A lipopolysaccharide(LPS)-induced inflammation model of zebrafish was established to evaluate the anti-inflammatory activity of aqueous extract and 70% ethanol extract of Saracae Cortex with cell apoptosis rate and reactive oxygen species(ROS) production rate as indicators. q PCR was performed to verify the main targets predicted by network pharmacology. The prediction found that there were 121 potential anti-inflammatory targets in Saracae Cortex. Protein-protein interaction(PPI) analysis showed that Saracae Cortex mainly acted on signal transducer and activator of transcription 3(STAT3), vascular endothelial growth factor A( VEGFA), epidermal growth factor( EGF), tumor necrosis factor( TNF),tumor protein p53(TP53), matrix metalloprotein 9(MMP9), c-fos proto-oncogene protein(FOS), estrogen receptor 1(ESR1), cx-c motif chemokine ligand 8(CXCL8), cluster of differentiation 8(CD8), and other targets. Gene Ontology(GO) analysis showed the biological process mainly acted on the inhibition of apoptosis, the positive regulation of gene expression, and the positive regulation of cell proliferation. Kyoto Encyclopedia of Genes and Genomes(KEGG) analysis showed that the mitogen-activated protein kinase(MAPK) signaling pathway, PI3K-Akt signaling pathway, and hypoxia-inducible factor 1(HIF-1) signaling pathway may play a key role in anti-inflammation of Saracae Cortex. Molecular docking verified that five key compounds had a strong binding force with their corresponding core target. Zebrafish animal experiments showed that Saracae Cortex could significantly inhibit ROS formation and reduce cell apoptosis in juvenile fish caused by inflammation and inhibit the further enhancement of inflammatory response in tissue. In addition, compared with the blank group, the transcription levels of nuclear factor kappa-B(NF-κB), TP53, FOS, adaptor protein complex-1(AP-1), and mitogen-activated protein kinases P38(P38) were significantly up-regulated in the model group. Compared with the model group, the m RNA expression of NF-κB, TP53, FOS, AP-1, and P38 was significantly down-regulated in zebrafish tissue treated with aqueous extract and 70% ethanol extract of Saracae Cortex. Saracae Cortex plays an anti-inflammatory role through multiple components and targets, and its anti-inflammatory effect may be related to the inhibition of the MAPK signaling pathway.

Potential mechanism of Chai Gui Zexie Decoction for NSCLC treatment assessed using network pharmacology, bioinformatics, and molecular docking: An observational study.

To explore the potential mechanism of Chai Gui Zexie Decoction for non-small cell lung cancer (NSCLC) treatment using network pharmacology, bioinformatics, and molecular docking. The active ingredients of Chai Gui Zexie Decoction and the associated predicted targets were screened using the TCMSP database. NSCLC-related targets were obtained from GeneCards and OMIM. Potential action targets, which are intersecting drug-predicted targets and disease targets, were obtained from Venny 2.1. The protein-protein interaction network was constructed by importing potential action targets into the STRING database, and the core action targets and core ingredients were obtained via topological analysis. The core action targets were entered into the Metascape database, and Gene Ontology annotation analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were performed. Differentially expressed genes were screened using the Gene Expression Omnibus, and the key targets were obtained by validating the core action targets. The key targets were input into The Tumor IMmune Estimation Resource for immune cell infiltration analysis. Finally, the molecular docking of key targets and core ingredients was performed. We obtained 60 active ingredients, 251 drug prediction targets, and 2133 NSCLC-related targets. Meanwhile, 147 potential action targets were obtained, and 47 core action targets and 40 core ingredients were obtained via topological analysis. We detected 175 pathways related to NSCLC pharmaceutical therapy. In total, 1249 Gene Ontology items were evaluated. Additionally, 3102 differential genes were screened, and tumor protein P53, Jun proto-oncogene, interleukin-6, and mitogen-activated protein kinase 3 were identified as the key targets. The expression of these key targets in NSCLC was correlated with macrophage, CD4+ T, CD8+ T, dendritic cell, and neutrophil infiltration. The molecular docking results revealed that the core ingredients have a potent affinity for the key targets. Chai Gui Zexie Decoction might exert its therapeutic effect on NSCLC through multiple ingredients, targets, and signaling pathways.

The Role of Speedy/RINGO Protein in Breast Cancer as a Future Biomarker.

Cyclin-dependent kinases (CDKs) are proteins that require the binding of regulatory subunits called cyclins and play a key role in cell cycle progression and activation. CDKs play a key role in carcinogenesis of many solid malignancies, and inhibition of these proteins has produced anti-cancer effects demonstrated in preclinical studies. This narrative review was conducted to develop a hypothetical approach to determine whether Speedy/RINGO, a protein associated with CDK2, could be a possible predictive factor in breast cancer patients treated with a CDK4/6 inhibitor. A literature search was conducted in PubMed, Web of Science, Medline, and Google Scholars search engines to match the following words: "Speedy/RINGO" or "Spy1" and "CDKs" or "Cyclin-dependent kinases (CDKs)" and "CDK4/6 inhibitors" and "Regulation" and "Molecular" and "Breast cancer" and "Carcinogenesis". Only articles investigating the relationship between the Speedy/RINGO protein and CDKs at the molecular level were included. Literature information was compiled by trying to establish a relationship with our hypothesis question. Speedy/RINGO is a tightly regulated proto-oncogenic mammalian protein playing important roles in the somatic cell cycle. Studies have emphasized that although it does not have amino acid sequence homology with cyclins, it can activate CDK2. In addition, results showing molecular compensation of CDK4/6 inhibition through CDK2 activation, also showed that CDK2 can predict drug resistance. Another important finding was that overexpressed Speedy/RINGO, during CDK4/6 inhibitor treatment, could strongly activate CDK2, resulting in a negative response to treatment. Although many predictive factors have been investigated to indicate response to CDK4/6 inhibitors or determine drug resistance, a consensus biomarker has yet to be established. In light of the information obtained from our review, it can be concluded that the Speedy/RINGO protein may have an important role as a predictive biomarker in terms of response to treatment, continuity of treatment and drug resistance in patients treated with CDK4/6 inhibitors.

Inhibition of protein translational machinery in triple-negative breast cancer as a promising therapeutic strategy

Y-box binding protein-1 (YB-1) is a proto-oncogenic protein associated with protein translation regulation. It plays a crucial role in the development and progression of triple-negative breast cancer (TNBC). In this study, we describe a promising approach to inhibit YB-1 using SU056, a small-molecule inhibitor. SU056 physically interacts with YB-1 and reduces its expression, which helps to restrain the progression of TNBC. Proteome profiling analysis indicates that the inhibition of YB-1 by SU056 can alter the proteins that regulate protein translation, an essential process for cancer cell growth. Preclinical studies on human cells, mice, and patient-derived xenograft tumor models show the effectiveness of SU056. Moreover, toxicological studies have shown that SU056 treatment and dosing are well tolerated without any adverse effects. Overall, our study provides a strong foundation for the further development of SU056 as a potential treatment option for patients with TNBC by targeting YB-1.

Active substance and mechanisms of Actinidia chinensis Planch for the treatment of breast cancer was explored based on network pharmacology and in silico study.

In this paper, our objective was to investigate the potential mechanisms of Actinidia chinensis Planch (ACP) for breast cancer treatment with the application of network pharmacology, molecular docking, and molecular dynamics. "Mihoutaogen" was used as a key word to query the Traditional Chinese Medicine Systems Pharmacology database for putative ingredients of ACP and its related targets. DrugBank, GeneCards, Online Mendelian Inheritance in Man, and therapeutic target databases were used to search for genes associated with "breast cancer." Using Cytoscape 3.9.0 we then constructed the protein-protein interaction and drug-ingredient-target-disease networks. An enrichment analysis of Kyoto encyclopedia of genes and genomes pathway and gene ontology were performed to exploration of the signaling pathways associated with ACP for breast cancer treatment. Discovery Studio software was applied to molecular docking. Finally, the ligand-receptor complex was subjected to a 50-ns molecular dynamics simulation using the Desmond_2020.4 tools. Six main active ingredients and 176 targets of ACP and 2243 targets of breast cancer were screened. There were 118 intersections of targets for both active ingredients and diseases. Tumor protein P53 (TP53), AKT serine/threonine kinase 1 (AKT1), estrogen receptor 1 (ESR1), Erb-B2 receptor tyrosine kinase 2 (ERBB2), epidermal growth factor receptor (EGFR), Jun Proto-Oncogene (JUN), and Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90AA1) selected as the most important genes were used for verification by molecular docking and molecular dynamics simulation. The primary active compounds of ACP against breast cancer were predicted preliminarily, and its mechanism was studied, thereby providing a theoretical basis for future clinical studies.

Identification of New Markers of Angiogenic Sprouting Using Transcriptomics: New Role for RND3.

New blood vessel formation requires endothelial cells to transition from a quiescent to an invasive phenotype. Transcriptional changes are vital for this switch, but a comprehensive genome-wide approach focused exclusively on endothelial cell sprout initiation has not been reported. Using a model of human endothelial cell sprout initiation, we developed a protocol to physically separate cells that initiate the process of new blood vessel formation (invading cells) from noninvading cells. We used this model to perform multiple transcriptomics analyses from independent donors to monitor endothelial gene expression changes. Single-cell population analyses, single-cell cluster analyses, and bulk RNA sequencing revealed common transcriptomic changes associated with invading cells. We also found that collagenase digestion used to isolate single cells upregulated the Fos proto-oncogene transcription factor. Exclusion of Fos proto-oncogene expressing cells revealed a gene signature consistent with activation of signal transduction, morphogenesis, and immune responses. Many of the genes were previously shown to regulate angiogenesis and included multiple tip cell markers. Upregulation of SNAI1 (snail family transcriptional repressor 1), PTGS2 (prostaglandin synthase 2), and JUNB (JunB proto-oncogene) protein expression was confirmed in invading cells, and silencing JunB and SNAI1 significantly reduced invasion responses. Separate studies investigated rounding 3, also known as RhoE, which has not yet been implicated in angiogenesis. Silencing rounding 3 reduced endothelial invasion distance as well as filopodia length, fitting with a pathfinding role for rounding 3 via regulation of filopodial extensions. Analysis of in vivo retinal angiogenesis in Rnd3 heterozygous mice confirmed a decrease in filopodial length compared with wild-type littermates. Validation of multiple genes, including rounding 3, revealed a functional role for this gene signature early in the angiogenic process. This study expands the list of genes associated with the acquisition of a tip cell phenotype during endothelial cell sprout initiation.

Direct-to-biology platform: From synthesis to biological evaluation of SHP2 allosteric inhibitors

Tyrosine phosphatase SHP2 is a proto-oncogenic protein involved in cell growth and differentiation via diverse intracellular signaling pathways. With the scope of identifying new SHP2 allosteric inhibitors, we report here the development and optimization of a high-throughput “Direct-to-Biology” (D2B) workflow including the synthesis and the biological evaluation of the reaction crude, thus eliminating the need for purification. During this labor-saving procedure, the structural diversity was introduced through a SNAr reaction. A wide array of analogues with good chemical purity was generated, allowing the obtention of reliable biological data which validated this efficient technique. This approach enabled the fast evaluation of a variety of structurally diverse fragments leading to nanomolar SHP2 allosteric inhibitors and a new series bearing a novel bicyclo[3.1.0]hexane moiety.

Hsp Inhibitor is Affective Against Adenocarcinomic Human Alveolar Basal Epithelial Cells Through Modulating ERK/MAPK Signaling Pathway.

The extracellular signal-regulated kinase (ERK) - mitogen-activated protein kinase (MAPK) pathway regulates cell proliferation, differentiation, and apoptosis. Heat Shock Protein 90 (HSP90) is required to activate proto-oncogenic protein kinases and promotes tumor growth through anti-apoptotic effects on A549-non-small cell lung cancer (NSCLC). Therefore, deregulation of the ERK-MAPK pathway and abnormal expression of HSP90 are reasonably frequent events in NSCLC. In this study, novel perimidine-pyrazole compounds employed to block ERK-MAPK deregulation through inhibiting HSP dependent cancer cell survival mechanisms. A set of perimidine-pyrazole derivatives effects was monitored on NSCLC cell line. Array experiments performed to understand the effect of the compounds on signaling pathways and results were analyzed by gene enrichment analysis. Further, senescence and apoptosis experiments were performed to support the enrichment results along with in silico methods to determine perimidine-pyrazole/HSP interactions. Treatment of NSCLC cells with perimidine-pyrazole derivatives displayed cancer-inhibitory, pro-senescent and pro-apoptotic effects on NSCLC cells through ERK/MAPK pathway and these compounds are promising templates for designing anticancer drugs.

Proto-oncogene Protein Sequence Classification using RNN and CNN with Attention Mechanism

Proto-oncogene Protein Sequence Classification using RNN and CNN with Attention Mechanism

Chelators as Antineuroblastomas Agents.

Neuroblastoma represents 8-10 % of all malignant tumors in childhood and is responsible for 15 % of cancer deaths in the pediatric population. Aggressive neuroblastomas are often resistant to chemotherapy. Canonically, neuroblastomas can be classified according to the MYCN (N-myc proto-oncogene protein) gene amplification, a common marker of tumor aggressiveness and poor prognosis. It has been found that certain compounds with chelating properties may show anticancer activity, but there is little evidence for the effect of chelators on neuroblastoma. The effect of new chelators characterized by the same functional group, designated as HLZ (1-hydrazino phthalazine), on proliferation (WST-1 and methylene blue assay), cell cycle (flow cytometry), apoptosis (proliferation assay after use of specific pharmacological inhibitors and western blot analysis) and ROS production (fluorometric assay based on dichlorofluorescein diacetate metabolism) was studied in three neuroblastoma cell lines with different levels of MYCN amplification. The molecules were effective only on MYCN-non-amplified cells in which they arrested the cell cycle in the G0/G1 phase. We investigated the mechanism of action and identified the activation of cell signaling that involves protein kinase C.

Posttreatment complications in pediatric cervical neuroblastoma: A retrospective case series at a tertiary cancer center.

Neuroblastomas rarely occur as primary tumors in the cervical region. Therefore, very little has been reported regarding treatment strategies, complications, and outcomes of these cervical neuroblastomas. The goal of this study is to review the presentation, management, and outcomes of all primary cervical pediatric neuroblastoma cases at a single tertiary care center. A retrospective cohort review of all neuroblastoma patients treated at a single center were performed. All patients with primary cervical neuroblastoma were reviewed for demographic information, tumor characteristics, treatment, and outcomes. Thirty (1.8%) patients were found to have undergone treatment for cervical neuroblastoma tumors diagnosed on average at 2.1 years old. Most presented with a swollen neck/palpable mass ± Horner's syndrome. Based on features including tumor staging, N-myc proto-oncogene protein (MYCN) amplification status, histology, most were deemed intermediate or high risk. Treatment strategies centered around chemotherapeutic regimens with surgery when possible as well as various adjuvant treatments including radiation therapy, immunotherapy, bone marrow transplant, and a neuroblastoma vaccine. Ten (33.3%) of patients experienced treatment-related complications and four (13.3%) died as a result of their disease progression. All four patients were high-risk patients, two of which had MYCN amplification. Cervical neuroblastomas generally have favorable outcomes. These tumors can be treated effectively with chemotherapy and surgical intervention with various adjuvant therapies. MYCN amplification and higher stage disease presentation contribute to worse outcomes.