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1.
Vet Q ; 44(1): 1-13, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38465827

RESUMO

Marek's disease virus (MDV) has become an increasingly virulent pathogen in the poultry industry despite vaccination efforts to control it. Brazil has experienced a significant rise of Marek's disease (MD) outbreaks in recent years. Our study aimed to analyze the complete meq gene sequences to understand the molecular epidemiological basis of MD outbreaks in Brazilian vaccinated layer farms. We detected a high incidence rate of visceral MD (67.74%) and multiple circulating MDV strains. The most prevalent and geographically widespread genotype presented several clinical and molecular characteristics of a highly virulent strain and evolving under positive selective pressure. Phylogenetic and phylogeographic analysis revealed a closer relationship with strains from the USA and Japan. This study sheds light on the circulation of MDV strains capable of infecting vaccinated birds. We emphasize the urgency of adopting preventive measures to manage MDV outbreaks threatening the poultry farming industry.


Assuntos
Mardivirus , Doença de Marek , Doenças das Aves Domésticas , Animais , Aves Domésticas , Galinhas/genética , Brasil/epidemiologia , Filogenia , Mardivirus/genética , Doença de Marek/epidemiologia , Doença de Marek/prevenção & controle , Doença de Marek/genética , Fazendas , Oncogenes , Doenças das Aves Domésticas/epidemiologia , Doenças das Aves Domésticas/prevenção & controle
2.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 42(1): 46-55, 2024 Feb 01.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38475950

RESUMO

OBJECTIVES: This study aimed to explore the effect of pituitary tumor-transforming gene 1 (PTT-G1) on the invasion and proliferation of oral squamous cell carcinoma (OSCC) cell lines under the action of miR-362-3p. METHODS: The bioinformatics online database was used to query the expression of PTTG1 in head and neck squamous cell carcinoma (HNSCC). The expression of PTTG1 in the Cal-27, HN-30, and HOK cell lines was detected by Western blot. A wound-healing assay was used to determine the effect of PTTG1 on the migration ability of the OSCC cells. The Transwell assay was used to examine the changes in cell-invasion ability. 5-ethynyl-2'-deoxyuridine (EdU) cell-proliferation assay was used to detect changes in cell-proliferation ability. Bioinformatics approach predicted the upstream miRNA of PTTG1. The targeting relationship between miR-362-3p and PTTG1 was examined by the dual luciferase assay, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the expression of miRNA in OSCC tissues. RESULTS: The ENCORI database showed that PTTG1 expression was up-regulated in OSCC tissues. Western blot confirmed that PTTG1 expression was up-regulated in Cal-27 and HN-30 cells than HOK cells. PTTG1 knockout can inhibit the migration, invasion, and proliferation of Cal-27 and HN-30 cells (P<0.05). Bioinformatics prediction websites predicted that the upstream miRNA of PTTG1 was miR-362-3p, and PTTG1 can bind to miR-362-3p. Results of qRT-PCR showed that miR-362-3p expression was downregulated in OSCC tissues compared with normal tissue (P<0.05). Transwell and EdU experiments confirmed that miR-362-3p knockdown can promote the invasion and proliferation of Cal-27 and HN-30 after PTTG1 knockdown. CONCLUSIONS: miR-362-3p can inhibit the invasion and proliferation of Cal-27 and HN-30 cells by targeting PTTG1.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , MicroRNAs , Neoplasias Bucais , Neoplasias Hipofisárias , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Carcinoma de Células Escamosas/genética , Neoplasias Bucais/genética , Neoplasias Hipofisárias/genética , Invasividade Neoplásica/genética , Movimento Celular/genética , MicroRNAs/genética , Proliferação de Células , Oncogenes , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica
3.
Int J Biol Sci ; 20(5): 1652-1668, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38481812

RESUMO

Liquid-liquid phase separation (LLPS) is a physiological phenomenon that parallels the mixing of oil and water, giving rise to compartments with diverse physical properties. Biomolecular condensates, arising from LLPS, serve as critical regulators of gene expression and control, with a particular significance in the context of malignant tumors. Recent investigations have unveiled the intimate connection between LLPS and cancer, a nexus that profoundly impacts various facets of cancer progression, including DNA repair, transcriptional regulation, oncogene expression, and the formation of critical membraneless organelles within the cancer microenvironment. This review provides a comprehensive account of the evolution of LLPS from the molecular to the pathological level. We explore the mechanisms by through which biomolecular condensates govern diverse cellular physiological processes, encompassing gene expression, transcriptional control, signal transduction, and responses to environmental stressors. Furthermore, we concentrate on potential therapeutic targets and the development of small-molecule inhibitors associated with LLPS in prevalent clinical malignancies. Understanding the role of LLPS and its interplay within the tumor milieu holds promise for enhancing cancer treatment strategies, particularly in overcoming drug resistance challenges. These insights offer innovative perspectives and support for advancing cancer therapy.


Assuntos
Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Reparo do DNA , Junções Comunicantes , Oncogenes , Microambiente Tumoral/genética
4.
Front Immunol ; 15: 1295305, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38481990

RESUMO

Introduction: Ubiquitination is a crucial biological mechanism in humans, essential for regulating vital biological processes, and has been recognized as a promising focus for cancer therapy. Our objective in this research was to discover potential enzymes associated with ubiquitination that may serve as therapeutic targets for individuals with esophageal carcinoma (ESCA). Methods: To identify genes linked to the prognosis of ESCA, we examined mRNA sequencing data from patients with ESCA in the TCGA database. Further investigation into the role of the candidate gene in ESCA was conducted through bioinformatic analyses. Subsequently, we carried out biological assays to assess its impact on ESCA development. Results: Through univariate Cox regression analysis, we identified Ubiquitin Conjugating Enzyme E2 B (UBE2B) as a potential gene associated with the prognosis of ESCA. UBE2B exhibited significant upregulation and was found to be correlated with survival outcomes in ESCA as well as other cancer types. Additionally, UBE2B was observed to be involved in various biological pathways linked to the development of ESCA, including TNF-a signaling via NF-κB, epithelial-mesenchymal transition, inflammatory response, and hypoxia. Moreover, immune-related pathways like B cell activation (GO: 0042113), B cell receptor signaling pathway (GO: 0050853) and B cell mediated immunity (GO:0019724) were also involved. It was found that high expression of UBE2B was correlated with the increase of several kinds of T cells (CD8 T cells, Th1 cells) and macrophages, while effector memory T cell (Tem) and Th17 cells decreased. Furthermore, UBE2B showed potential as a prognostic biomarker for ESCA, displaying high sensitivity and specificity. Notably, proliferation and migration in ESCA cells were effectively suppressed when the expression of UBE2B was knocked down. Conclusions: To summarize, this study has made a discovery regarding the importance of gaining new insights into the role of UBE2B in ESCA. UBE2B might be an oncogene with good ability in predicting and diagnosing ESCA. Consequently, this discovery highlights the feasibility of targeting UBE2B as a viable approach for treating patients with ESCA.


Assuntos
Carcinoma , Neoplasias Esofágicas , Humanos , Prognóstico , Oncogenes , Linfócitos B , Neoplasias Esofágicas/genética , Biomarcadores , Enzimas de Conjugação de Ubiquitina/genética
5.
J Exp Clin Cancer Res ; 43(1): 68, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38439082

RESUMO

BACKGROUND: Proteasome inhibitors (PIs) are one of the most important classes of drugs for the treatment of multiple myeloma (MM). However, almost all patients with MM develop PI resistance, resulting in therapeutic failure. Therefore, the mechanisms underlying PI resistance in MM require further investigation. METHODS: We used several MM cell lines to establish PI-resistant MM cell lines. We performed RNA microarray and EccDNA-seq in MM cell lines and collected human primary MM samples to explore gene profiles. We evaluated the effect of MUC20 on cuproptosis of PI-resistant MM cells using Co-immunoprecipitation (Co-IP), Seahorse bioenergetic profiling and in vivo assay. RESULTS: This study revealed that the downregulation of Mucin 20 (MUC20) could predict PI sensitivity and outcomes in MM patients. Besides, MUC20 attenuated PI resistance in MM cells by inducing cuproptosis via the inhibition of cyclin-dependent kinase inhibitor 2 A expression (CDKN2A), which was achieved by hindering MET proto-oncogene, receptor tyrosine kinase (MET) activation. Moreover, MUC20 suppressed MET activation by repressing insulin-like growth factor receptor-1 (IGF-1R) lactylation in PI-resistant MM cells. This study is the first to perform extrachromosomal circular DNA (eccDNA) sequencing for MM, and it revealed that eccDNA induced PI resistance by amplifying kinesin family member 3 C (KIF3C) to reduce MUC20 expression in MM. CONCLUSION: Our findings indicated that MUC20 regulated by eccDNA alleviates PI resistance of MM by modulating cuproptosis, which would provide novel strategies for the treatment of PI-resistant MM.


Assuntos
Mieloma Múltiplo , Inibidores de Proteassoma , Humanos , Inibidores de Proteassoma/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Oncogenes , Citoplasma , Antivirais , DNA , DNA Circular , Cinesinas , Mucinas
6.
J Exp Clin Cancer Res ; 43(1): 69, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38443991

RESUMO

BACKGROUND: Head and neck squamous carcinoma (HNSCC) is known for its high aggressiveness and susceptibility to cervical lymph node metastasis, which greatly contributes to its poor prognosis. During tumorigenesis, many types of cancer cells acquire oncogenic super-enhancers (SEs) that drive the overexpression of oncogenes, thereby maintaining malignant progression. This study aimed to identify and validate the role of oncogenic SE-associated genes in the malignant progression of HNSCC. METHODS: We identified HNSCC cell-specific SE-associated genes through H3K27Ac ChIP-seq and overlapped them with HNSCC-associated genes obtained from The Cancer Genome Atlas (TCGA) dataset and Gene Expression Omnibus (GEO) datasets using weighted gene coexpression network analysis (WGCNA) to identify hub genes. The expression of IGF2BP2 and KLF7 in HNSCC was detected using clinical samples. To determine the biological role of IGF2BP2, we performed CCK-8, colony formation assay, Transwell migration assay, invasion assay, and orthotopic xenograft model experiments. Furthermore, we utilized a CRISPR/Cas9 gene-editing system, small-molecule inhibitors, ChIP-qPCR, and dual-luciferase reporter assays to investigate the molecular mechanisms of IGF2BP2 and its upstream transcription factors. RESULTS: Our study identified IGF2BP2 as a hub SE-associated gene that exhibited aberrant expression in HNSCC tissues. Increased expression of IGF2BP2 was observed to be linked with malignant progression and unfavorable prognosis in HNSCC patients. Both in vitro and in vivo experiments confirmed that IGF2BP2 promotes the tumorigenicity and metastasis of HNSCC by promoting cell proliferation, migration, and invasion. Mechanistically, the IGF2BP2-SE region displayed enrichment for H3K27Ac, BRD4, and MED1, which led to the inhibition of IGF2BP2 transcription and expression through deactivation of the SE-associated transcriptional program. Additionally, KLF7 was found to induce the transcription of IGF2BP2 and directly bind to its promoter and SE regions. Moreover, the abundance of KLF7 exhibited a positive correlation with the abundance of IGF2BP2 in HNSCC. Patients with high expression of both KLF7 and IGF2BP2 showed poorer prognosis. Lastly, we demonstrated that the small molecule inhibitor JQ1, targeting BRD4, attenuated the proliferation and metastatic abilities of HNSCC cells. CONCLUSIONS: Our study reveals the critical role of IGF2BP2 overexpression mediated by SE and KLF7 in promoting HNSCC progression. Targeting SE-associated transcriptional programs may represent a potential therapeutic strategy in managing HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço , Proteínas Nucleares , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Fatores de Transcrição , Oncogenes , Neoplasias de Cabeça e Pescoço/genética , Fatores de Transcrição Kruppel-Like/genética , Proteínas de Ligação a RNA , Proteínas que Contêm Bromodomínio , Proteínas de Ciclo Celular
7.
Commun Biol ; 7(1): 266, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38438584

RESUMO

Long noncoding RNA small nucleolar RNA host gene 5 (SNHG5) is an oncogene found in various human cancers. However, it is unclear what role SNHG5 plays in activating hepatic stellate cells (HSCs) and liver fibrosis. In this study, SNHG5 was found to be upregulated in activated HSCs in vitro and in primary HSCs isolated from fibrotic liver in vivo, and inhibition of SNHG5 suppressed HSC activation. Notably, Neurofibromin 2 (NF2), the main activator for Hippo signalling, was involved in the effects of SNHG5 on HSC activation. The interaction between SNHG5 and NF2 protein was further confirmed, and preventing the combination of the two could effectively block the effects of SNHG5 inhibition on EMT process and Hippo signaling. Additionally, higher SNHG5 was found in chronic hepatitis B patients and associated with the fibrosis stage. Altogether, we demonstrate that SNHG5 could serve as an activated HSCs regulator via regulating NF2 and Hippo pathway.


Assuntos
Neurofibromina 2 , RNA Longo não Codificante , Humanos , Células Estreladas do Fígado , Via de Sinalização Hippo , Cirrose Hepática/genética , Neurofibromina 2/genética , Oncogenes , RNA Longo não Codificante/genética
8.
BMC Bioinformatics ; 25(1): 99, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38448819

RESUMO

BACKGROUND: Cancer, a disease with high morbidity and mortality rates, poses a significant threat to human health. Driver genes, which harbor mutations accountable for the initiation and progression of tumors, play a crucial role in cancer development. Identifying driver genes stands as a paramount objective in cancer research and precision medicine. RESULTS: In the present work, we propose a method for identifying driver genes using a Generalized Linear Regression Model (GLM) with Shrinkage and double-Weighted strategies based on Functional Impact, which is named GSW-FI. Firstly, an estimating model is proposed for assessing the background functional impacts of genes based on GLM, utilizing gene features as predictors. Secondly, the shrinkage and double-weighted strategies as two revising approaches are integrated to ensure the rationality of the identified driver genes. Lastly, a statistical method of hypothesis testing is designed to identify driver genes by leveraging the estimated background function impacts. Experimental results conducted on 31 The Cancer Genome Altas datasets demonstrate that GSW-FI outperforms ten other prediction methods in terms of the overlap fraction with well-known databases and consensus predictions among different methods. CONCLUSIONS: GSW-FI presents a novel approach that efficiently identifies driver genes with functional impact mutations using computational methods, thereby advancing the development of precision medicine for cancer.


Assuntos
Neoplasias , Oncogenes , Humanos , Mutação , Cognição , Consenso , Bases de Dados Factuais , Neoplasias/genética
9.
Funct Integr Genomics ; 24(2): 52, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38448654

RESUMO

Long non-coding RNAs (lncRNAs) appear to be the crucial modulators in various processes and critically influence the oncogenesis. As one of the LncRNAs, LncRNA CCAT1 has been reported to be closely associated with the progression multiple cancers, but its role in modulating the radioresistance of lung adenocarcinoma (LUAD) remains unclear. In our present study, we screened the potential radioresistance related LncRNAs in LUAD based on the data from The Cancer Genome Atlas (TCGA) database. Data suggested that CCAT1 was abundantly expressed in LUAD and CCAT1 was significantly associated with poor prognosis and radioresistance. Moreover, our in vitro experiments showed that radiation treatment could trigger elevated expression of CCAT1 in the human LUAD cell lines. Further loss/gain-of-function investigations indicated that CCAT1 knockdown significantly inhibited cell proliferation, migration and promoted cell apoptosis in NCI-H1299 cells under irradiation, whereas CCAT1 overexpression in A549 cells yield the opposite effects. In summary, we identified the promoting role of CCAT1 in radioresistance of LUAD, which may provide a theoretical basis for radiotherapy sensitization of LUAD.


Assuntos
Adenocarcinoma , RNA Longo não Codificante , Humanos , Adenocarcinoma/genética , Adenocarcinoma/radioterapia , Epigenômica , Pulmão , Oncogenes , RNA Longo não Codificante/genética
10.
J Int Med Res ; 52(3): 3000605241233160, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38456653

RESUMO

BACKGROUND: Pancreatic cancer is a malignant tumor of the digestive tract that shows increased mortality, recurrence, and morbidity year on year. METHODS: Differentially expressed genes between pancreatic cancer and healthy tissues were first analyzed from four datasets within the Gene Expression Omnibus (GEO). Gene ontology, disease ontology, and gene set enrichment analysis of differentially expressed genes were performed, and genes identified as characteristic of pancreatic cancer were screened using LASSO regression combined with support vector machine and recursive feature elimination (SVM-RFE). Differential analysis and receiver operating characteristic curve analysis were performed on the identified eigengenes, and validation was carried out using another dataset from the GEO database. Differences and correlations between characteristic pancreatic cancer genes and immune cells were analyzed. RESULTS: A total of 90 differentially expressed genes were identified by screening, and six genes characteristic of pancreatic cancer were obtained by taking the intersection of two characteristic genes identified by machine learning. Immunoassays yielded multiple immune cells associated with pancreatic cancer signature genes. CONCLUSION: The six characteristic genes screened by a combination of LASSO regression and SVM-RFE are potential new biomarkers for the early diagnosis and prognosis of pancreatic cancer, and could be a novel therapeutic target.


Assuntos
Detecção Precoce de Câncer , Neoplasias Pancreáticas , Humanos , Máquina de Vetores de Suporte , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Oncogenes , Pâncreas
11.
Zhonghua Zhong Liu Za Zhi ; 46(3): 211-220, 2024 Mar 23.
Artigo em Chinês | MEDLINE | ID: mdl-38494768

RESUMO

Antibody-drug conjugates (ADCs) are drugs that combine monoclonal antibody drugs targeting specific antigens and small molecule cytotoxic drugs through linker molecules. ADCs combine the advantages of high specificity targeting and potent killing effects, achieving precise and efficient targeting of cancer cells. Nowadays, ADCs are one of the hotspots in cancer drug development. Human epidermal growth factor receptor 2 (HER-2) is a known oncogene that can drive the occurrence and development of various types of tumors. HER-2 is also an important tumor target for ADCs approved for solid tumors. Anti-HER-2 ADCs can not only be used to treat HER-2-positive tumors but also effectively target HER-2-low tumors. The emergence of ADCs has broken the traditional classification of HER-2 in tumors, bringing significant treatment breakthroughs for HER-2-low tumors. Anti-HER-2 ADCs are widely used in the treatment of solid tumors and have substantial evidence for HER-2-low tumors. This article presents the progress of various anti-HER-2 ADCs in HER-2-low tumors including breast cancer, gastrointestinal malignancies, urothelial carcinoma, lung cancer. And this article summarizes the current status of preclinical studies, clinical studies, and safety of anti-HER-2 ADCs in order to provide reference for the clinical use of HER-2-low tumors.


Assuntos
Antineoplásicos , Carcinoma de Células de Transição , Imunoconjugados , Receptor ErbB-2 , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Antineoplásicos/uso terapêutico , Imunoconjugados/uso terapêutico , Oncogenes
12.
Comput Biol Med ; 171: 108234, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38430742

RESUMO

Breast cancer has become a severe public health concern and one of the leading causes of cancer-related death in women worldwide. Several genes and mutations in these genes linked to breast cancer have been identified using sophisticated techniques, despite the fact that the exact cause of breast cancer is still unknown. A commonly used feature for identifying driver mutations is the recurrence of a mutation in patients. Nevertheless, some mutations are more likely to occur than others for various reasons. Sequencing analysis has shown that cancer-driving genes operate across complex networks, often with mutations appearing in a modular pattern. In this work, as a retrospective study, we used TCGA data, which is gathered from breast cancer patients. We introduced a new machine-learning approach to examine gene functionality in networks derived from mutation associations, gene-gene interactions, and graph clustering for breast cancer analysis. These networks have uncovered crucial biological components in critical pathways, particularly those that exhibit low-frequency mutations. The statistical strength of the clinical study is significantly boosted by evaluating the network as a whole instead of just single gene effects. Our method successfully identified essential driver genes with diverse mutation frequencies. We then explored the functions of these potential driver genes and their related pathways. By uncovering low-frequency genes, we shed light on understudied pathways associated with breast cancer. Additionally, we present a novel Monte Carlo-based algorithm to identify driver modules in breast cancer. Our findings highlight the significance and role of these modules in critical signaling pathways in breast cancer, providing a comprehensive understanding of breast cancer development. Materials and implementations are available at: [https://github.com/MahnazHabibi/BreastCancer].


Assuntos
Neoplasias da Mama , Neoplasias , Humanos , Feminino , Neoplasias da Mama/genética , Estudos Retrospectivos , Oncogenes , Mutação/genética , Neoplasias/genética , Aprendizado de Máquina , Redes Reguladoras de Genes
13.
PLoS One ; 19(3): e0296779, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38478555

RESUMO

The mitotic spindle is the bipolar, microtubule-based structure that segregates chromosomes at each cell division. Aberrant spindles are frequently observed in cancer cells, but how oncogenic transformation affects spindle mechanics and function, particularly in the mechanical context of solid tumors, remains poorly understood. Here, we constitutively overexpress the oncogene cyclin D1 in human MCF10A cells to probe its effects on spindle architecture and response to compressive force. We find that cyclin D1 overexpression increases the incidence of spindles with extra poles, centrioles, and chromosomes. However, it also protects spindle poles from fracturing under compressive force, a deleterious outcome linked to multipolar cell divisions. Our findings suggest that cyclin D1 overexpression may adapt cells to increased compressive stress, possibly contributing to its prevalence in cancers such as breast cancer by allowing continued proliferation in mechanically challenging environments.


Assuntos
Centrossomo , Ciclina D1 , Humanos , Centríolos , Ciclina D1/genética , Mitose , Oncogenes , Fuso Acromático/genética
14.
Nat Commun ; 15(1): 2531, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38514704

RESUMO

YEATS domain-containing protein GAS41 is a histone reader and oncogene. Here, through genome-wide CRISPR-Cas9 screenings, we identify GAS41 as a repressor of ferroptosis. GAS41 interacts with NRF2 and is critical for NRF2 to activate its targets such as SLC7A11 for modulating ferroptosis. By recognizing the H3K27-acetylation (H3K27-ac) marker, GAS41 is recruited to the SLC7A11 promoter, independent of NRF2 binding. By bridging the interaction between NRF2 and the H3K27-ac marker, GAS41 acts as an anchor for NRF2 on chromatin in a promoter-specific manner for transcriptional activation. Moreover, the GAS41-mediated effect on ferroptosis contributes to its oncogenic role in vivo. These data demonstrate that GAS41 is a target for modulating tumor growth through ferroptosis. Our study reveals a mechanism for GAS41-mediated regulation in transcription by anchoring NRF2 on chromatin, and provides a model in which the DNA binding activity on chromatin by transcriptional factors (NRF2) can be directly regulated by histone markers (H3K27-ac).


Assuntos
Ferroptose , Histonas , Histonas/metabolismo , Cromatina/genética , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ferroptose/genética , Oncogenes
15.
Aging (Albany NY) ; 16(5): 4469-4502, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38441550

RESUMO

BACKGROUND: Prostate cancer is the most common malignancy among men worldwide, and its diagnosis and treatment are challenging due to its heterogeneity. METHODS: Integrating single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data, we identified two molecular subtypes of prostate cancer based on dysregulated genes involved in oxidative stress and energy metabolism. We constructed a risk score model (OMR) using common differentially expressed genes, which effectively evaluated prostate cancer prognosis. RESULTS: Our analysis demonstrated a significant correlation between the risk score model and various factors, including tumor immune microenvironment, genomic variations, chemotherapy resistance, and immune response. Notably, patients with low-risk scores exhibited increased sensitivity to chemotherapy and immunotherapy compared to those with high-risk scores, indicating the model's potential to predict patient response to treatment. Additionally, our investigation of MXRA8 in prostate cancer showed significant upregulation of this gene in the disease as confirmed by PCR and immunohistochemistry. Functional assays including CCK-8, transwell, plate cloning, and ROS generation assay demonstrated that depletion of MXRA8 reduced the proliferative, invasive, migratory capabilities of PC-3 cells, as well as their ROS generation capacity. CONCLUSIONS: Our study highlights the potential of oxidative stress and energy metabolism-related genes as prognostic markers and therapeutic targets in prostate cancer. The integration of scRNA-seq and bulk RNA-seq data enables a better understanding of prostate cancer heterogeneity and promotes personalized treatment development. Additionally, we identified a novel oncogene MXRA8 in prostate cancer.


Assuntos
Oncogenes , Neoplasias da Próstata , Humanos , Masculino , Metabolismo Energético/genética , Estresse Oxidativo/genética , Prognóstico , Neoplasias da Próstata/genética , Espécies Reativas de Oxigênio , Microambiente Tumoral/genética , Proteínas de Membrana/genética , Imunoglobulinas/genética
16.
Clin Adv Hematol Oncol ; 22(2): 67-75, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38446474

RESUMO

Kirsten rat sarcoma virus (KRAS) is the most frequently mutated oncogene in human cancers, particularly in non-small cell lung cancer (NSCLC), where mutations are present in 32% of lung adenocarcinoma and 4% of squamous cell lung cancer. The most common KRAS variant is KRAS G12C, which accounts for nearly 40% of all KRAS mutations. Although it is the most common oncogenic driver in NSCLC, KRAS was considered a "nondruggable target" until recently, owing to the lack of any progress in developing targeted therapies for this oncogene. With the recent development and approval of selective KRAS G12C inhibitors such as sotorasib and adagrasib for the treatment of advanced or metastatic NSCLC in the second-line setting and beyond, the standard of care for managing these tumors has undergone a significant change. Mechanisms of resistance to KRAS G12C inhibitors are highly heterogeneous, including both on-target and off-target resistance as well as morphologic switching, thus limiting the activity of these drugs when used as monotherapy. New-generation inhibitors and different combination strategies are being developed in early-phase trials to overcome or delay the onset of resistance as well as to target non-G12C mutations. Owing to the biological heterogeneity of KRAS-mutant NSCLC, treatment will likely need to be individualized based on factors such as co-occurring mutations.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Oncogenes
17.
Front Immunol ; 15: 1324679, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38500873

RESUMO

Introduction: PU.1-mutated agammaglobulinemia (PU.MA) represents a recently described autosomal-dominant form of agammaglobulinemia caused by mutation of the SPI1 gene. This gene codes for PU.1 pioneer transcription factor important for the maturation of monocytes, B lymphocytes, and conventional dendritic cells. Only six cases with PU.MA, presenting with chronic sinopulmonary and systemic enteroviral infections, have been previously described. Accumulating literature evidence suggests a possible relationship between SPI1 mutation, microglial phagocytic dysfunction, and the development of Alzheimer's disease (AD). Case description: We present a Caucasian female patient born from a non-consanguineous marriage, who was diagnosed with agammaglobulinemia at the age of 15 years when the immunoglobulin replacement therapy was started. During the following seventeen years, she was treated for recurrent respiratory and intestinal infections. At the age of 33 years, the diagnosis of celiac-like disease was established. Five years later progressive cognitive deterioration, unstable gait, speech disturbances, and behavioral changes developed. Comprehensive microbiological investigations were negative, excluding possible infective etiology. Brain MRI, 18FDG-PET-CT, and neuropsychological testing were suggestive for a diagnosis of a frontal variant of AD. Clinical exome sequencing revealed the presence of a novel frameshift heterozygous variant c.441dup in exon 4 of the SPI1 gene. Despite intensive therapy, the patient passed away a few months after the onset of the first neurological symptoms. Conclusion: We describe the first case of PU.MA patient presenting with a rapidly progressive neurocognitive deterioration. The possible role of microglial dysfunction in patients with SPI1 mutation could explain their susceptibility to neurodegenerative diseases thus highlighting the importance of genetic testing in patients with inborn errors of immunity. Since PU.MA represents a newly described form of agammaglobulinemia, our case expands the spectrum of manifestations associated with SPI1 mutation.


Assuntos
Agamaglobulinemia , Doença de Alzheimer , Humanos , Feminino , Adolescente , Adulto , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Agamaglobulinemia/complicações , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Oncogenes , Doença de Alzheimer/genética
18.
Nat Commun ; 15(1): 1768, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38409079

RESUMO

Extrachromosomal circular DNAs (eccDNAs) have emerged as important intra-cellular mobile genetic elements that affect gene copy number and exert in trans regulatory roles within the cell nucleus. Here, we describe scCircle-seq, a method for profiling eccDNAs and unraveling their diversity and complexity in single cells. We implement and validate scCircle-seq in normal and cancer cell lines, demonstrating that most eccDNAs vary largely between cells and are stochastically inherited during cell division, although their genomic landscape is cell type-specific and can be used to accurately cluster cells of the same origin. eccDNAs are preferentially produced from chromatin regions enriched in H3K9me3 and H3K27me3 histone marks and are induced during replication stress conditions. Concomitant sequencing of eccDNAs and RNA from the same cell uncovers the absence of correlation between eccDNA copy number and gene expression levels, except for a few oncogenes, including MYC, contained within a large eccDNA in colorectal cancer cells. Lastly, we apply scCircle-seq to one prostate cancer and two breast cancer specimens, revealing cancer-specific eccDNA landscapes and a higher propensity of eccDNAs to form in amplified genomic regions. scCircle-seq is a scalable tool that can be used to dissect the complexity of eccDNAs across different cell and tissue types, and further expands the potential of eccDNAs for cancer diagnostics.


Assuntos
DNA Circular , DNA , Masculino , Humanos , DNA Circular/genética , Cromossomos , Linhagem Celular , Oncogenes
19.
Biomed Pharmacother ; 172: 116221, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38306843

RESUMO

The gene therapy attracted more and more attention for the tumor therapy. To obtain a safe gene therapy system, the new gene vectors beyond the virus were developed for a high gene therapy efficiency. The ultrasound mediated gene therapy was safer and the plasmid DNA could be delivered by the microbubbles and combined with the ultrasound to increase the gene transfection efficiency. In this work, the cationic microbubbles decorated with Cyclo(Cys-Arg-Gly-Asp-Lys-Gly-Pro-AspCys) (iRGD peptides) and magnetic Fe3O4 nanoparticles (MBiM) was designed for targeted ultrasound contrast imaging guided gene therapy of tumors. The ultrasound image intensity was dramatically enhanced at the tumor site that received MBiM with the magnet applied, compared to those administrated the non-targeted microbubbles (MBb) or the microbubbles with only one target material on the surface (MBM and MBbi). The pGPU6/GFP/Neo-shAKT2 was used as a sample gene, which down regulate the AKT2 protein expression for the cancer therapy. It illustrated that MBiM/AKT2 had the highest gene transfection efficiency in the studied microbubbles mediated by the ultrasound, leading to the AKT2 protein expression downregulation and the strongest tumor killing effect in vitro and in vivo. In summary, a novel and biocompatible gene delivery platform via MBiM with both the endogenous and external targeting effects for breast cancer theranostics was developed.


Assuntos
Neoplasias da Mama , Microbolhas , Humanos , Feminino , Ultrassonografia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Oncogenes , Fenômenos Magnéticos
20.
Cancer Med ; 13(3): e6852, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38308423

RESUMO

OBJECTIVE: Turkish genome is underrepresented in large genomic databases. This study aims to evaluate the effect of allele frequency in the Turkish population in determining the clinical utility of germline findings in breast cancer, including invasive lobular carcinoma (ILC), mixed invasive ductal and lobular carcinoma (IDC-L), and ductal carcinoma (DC). METHODS: Two clinic-based cohorts from the Umraniye Research and Training Hospital (URTH) were used in this study: a cohort consisting of 132 women with breast cancer and a non-cancer cohort consisting of 492 participants. The evaluation of the germline landscape was performed by analysis of 27 cancer genes. The frequency and type of variants in the breast cancer cohort were compared to those in the non-cancer cohort to investigate the effect of population genetics. The variant allele frequencies in Turkish Variome and gnomAD were statistically evaluated. RESULTS: The genetic analysis identified 121 variants in the breast cancer cohort (actionable = 32, VUS = 89) and 223 variants in the non-cancer cohort (actionable = 25, VUS = 188). The occurrence of 21 variants in both suggested a possible genetic population effect. Evaluation of allele frequency of 121 variants from the breast cancer cohort showed 22% had a significantly higher value in Turkish Variome compared to gnomAD (p < 0.0001, 95% CI) with a mean difference of 60 times (ranging from 1.37-354.4). After adjusting for variant allele frequency using the ancestry-appropriate database, 6.7% (5/75) of VUS was reclassified to likely benign. CONCLUSION: To our knowledge, this is the first study of population genetic effects in breast cancer subtypes in Turkish women. Our findings underscore the need for a large genomic database representing Turkish population-specific variants. It further highlights the significance of the ancestry-appropriate population database for accurate variant assessment in clinical settings.


Assuntos
Neoplasias da Mama , Carcinoma Ductal de Mama , Carcinoma Lobular , Humanos , Feminino , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Genômica , Oncogenes
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