RESUMO
Circular RNAs (circRNAs) have been identified as important mediators of tumorigenesis and tumor progression. This study focuses on circAGFG1, a circRNA with elevated N6-methyladenosine (m6A) modification, and its role in triple-negative breast cancer (TNBC). Fluorescence in situ hybridization and qPCR analyses revealed that circAGFG1 is significantly upregulated in TNBC tissues and in the TNBC cell line MDA-MB-231. Functional characterization using loss-of-function and gain-of-function strategies in two TNBC cell lines demonstrated that circAGFG1 promotes oncogenic phenotypes. Specifically, knockdown in MDA-MB-231 cells suppressed proliferation, invasion, migration, and G1/S phase transition, while its overexpression in MDA-MB-468 cells promoted these processes. Mechanistically, western blotting and PCR analyses indicated that circAGFG1 modulates the expression of epithelial-mesenchymal transition markers N-cadherin and α-SMA. Furthermore, we identified that YTHDF3, an m6A reader protein upregulated in TNBC, upregulates circAGFG1 expression by enhancing its transcript stability. Finally, dual-luciferase reporter assays confirmed that circAGFG1 acts as a sponge for miR-1299, thereby potentially modulating the miR-1299 signaling pathway. Collectively, our findings delineate the critical role of the circAGFG1 in promoting TNBC progression, highlighting its potential as a novel therapeutic target.
Assuntos
Oncogenes , RNA Circular , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Feminino , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Oncogenes/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Regulação para Cima , Adenosina/análogos & derivadosRESUMO
Myeloid leukemias, diseases marked by aggressiveness and poor outcomes, are frequently triggered by oncogenic translocations. In the case of chronic myelogenous leukemia (CML), the BCR-ABL fusion initiates chronic phase disease with second hits allowing progression to blast crisis. Although Gleevec has been transformative for CML, blast crisis CML remains relatively drug resistant. Here, we show that MSI2-HOXA9, a translocation with an unknown role in cancer, can serve as a second hit in driving bcCML. Compared to BCR-ABL, BCR-ABL/MSI2-HOXA9 led to a more aggressive disease in vivo with decreased latency, increased lethality, and a differentiation blockade that is a hallmark of blast crisis. Domain mapping revealed that the MSI2 RNA binding domain RRM1 had a preferential impact on growth and lethality of bcCML relative to RRM2 or the HOXA9 domain. Mechanistically, MSI2-HOXA9 triggered global downstream changes with a preferential upregulation of mitochondrial components. Consistent with this, BCR-ABL/MSI2-HOXA9 cells exhibited a significant increase in mitochondrial respiration. These data suggest that MSI2-HOXA9 acts, at least in part, by increasing expression of the mitochondrial polymerase POLRMT and augmenting mitochondrial function and basal respiration in blast crisis. Collectively, our findings demonstrate for the first time that translocations involving the stem and developmental signal MSI2 can be oncogenic and suggest that MSI, which we found to be a frequent partner for an array of translocations, could also be a driver mutation across solid cancers.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide , Oncogenes , Proteínas de Ligação a RNA , Translocação Genética , Humanos , Animais , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Camundongos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Linhagem Celular Tumoral , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Leucemia Mieloide/genéticaRESUMO
ecDNA is a circular DNA extensively present in human cancers, particularly advanced tumors, but rarely detected in healthy cells. Previously, they were named "minute chromatin bodies," which eventually changed into "Double minutes (DMs)" as they exist in pairs. Due to their structural and epigenetic modifications, they confer specific advantages, helping them to survive and persist within cells. Rapid amplification of drug-resistant genes or oncogenes, increased chromatin accessibility, and non-Mendelian inheritance all contribute significantly to tumor adaptability, aggressiveness, and resistance to drug or chemotherapy treatment. Thus, this review paper aims to discuss DMs' formation, mechanism, and maintenance, examining the tools used to detect them and investigating the commonly observed oncogenes in different cancer types. Lastly, the therapeutic approaches applied over the years have been to reduce or eliminate DMs in tumor cells.
Assuntos
Carcinogênese , Cromatina , Neoplasias , Oncogenes , Humanos , Neoplasias/genética , Neoplasias/patologia , Progressão da Doença , Cromatina/genética , Cromatina/metabolismo , Epigênese Genética , Animais , Carcinogênese/genética , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
PURPOSE: The study aimed to investigate CDKN3 as a potential target for triple negative breast cancer (TNBC) and its mechanism in this type of cancer. METHODS: After lentiviral transfection, various assays, including CCK8, clonogenic assay, flow cytometry, transwell, and scratch tests were conducted. Additionally, we examined CDKN3's impact on iron-induced cell death through various cellular markers and iron-related proteins. To assess CDKN3's impact on ferroptosis, we utilized the ferroptosis inhibitor Ferrostatin-1 and activator Erastin. To examine CDKN3's involvement in iron-induced cell death in TNBC, we repeated the previous experiment after introducing an HSP90 inhibitor. A 4T1 mammary fat pad graft tumor model was also conducted to validate the results of our in vitro cellular experiments. RESULTS: In vitro experiments demonstrated that overexpression of CDKN3 promoted the growth, invasion, and migration of breast cancer cells. It also facilitated cell cycle progression from G0/G1 phase to S phase and suppressed apoptosis in TNBC cells. The knockdown of CDKN3 was the exact opposite. Overexpression of CDKN3 increased HSP90 expression, while CDKN3 knockdown decreased HSP90 expression. The impact of CDKN3 on the proliferation, migration, invasion, and ferroptosis of TNBC cells was associated with HSP90. The in vivo and in vitro experimental results were consistent, showing that CDKN3 overexpression promoted tumor growth and inhibited ferroptosis. CONCLUSION: CDKN3 was an oncogene whose overexpression promoted the initiation and progression of TNBC by inhibiting HSP90-mediated ferroptosis.
Assuntos
Proteínas Inibidoras de Quinase Dependente de Ciclina , Ferroptose , Proteínas de Choque Térmico HSP90 , Neoplasias Mamárias Experimentais , Neoplasias de Mama Triplo Negativas , Animais , Feminino , Camundongos , Linhagem Celular Tumoral , Proteínas Inibidoras de Quinase Dependente de Ciclina/genética , Proteínas Inibidoras de Quinase Dependente de Ciclina/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Neoplasias Mamárias Experimentais/etiologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia de Alvo Molecular , Distribuição Aleatória , Neoplasias de Mama Triplo Negativas/etiologia , Regulação para Cima , Oncogenes , Proteínas Tirosina FosfatasesRESUMO
Evidence implicates the Duchenne muscular dystrophy gene (DMD) in tumorigenesis, but survival trends are inconsistent. To resolve this, we conducted a comprehensive global analysis of DMD expression and survival outcomes across 33 tumour types using bulk RNA sequencing data from The Cancer Genome Atlas. We examined the impact of total DMD, individual transcript and dystrophin-associated protein complex (DAPC) gene expression levels on overall survival using Kaplan-Meier analysis, Cox proportional hazard modelling and pathway analysis. DMD expression was significantly associated with survival in nine cancers after Bonferroni correction (α = 0.0015), with high expression linked to either improved or worsened outcomes depending on cancer type. The most abundant DMD transcript, Dp71ab, mirrored total DMD trends, distinguishing two tumour groups with opposing survival associations. Hierarchical clustering suggests these divergent effects may be linked to a subset of signalling and adhesion-related DAPC components. Our findings indicate that DMD does not act uniformly as an oncogene or tumour suppressor. Instead, we propose a context-dependent dual model whereby high DMD expression is tumour suppressive in aggressive cancers and oncogenic in less aggressive tumours.
Assuntos
Distrofina , Distrofia Muscular de Duchenne , Neoplasias , Humanos , Distrofia Muscular de Duchenne/genética , Distrofina/genética , Distrofina/metabolismo , Neoplasias/genética , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Estimativa de Kaplan-Meier , Genes Supressores de Tumor , Oncogenes/genéticaRESUMO
An aggressive subtype of acute myeloid leukemia (AML) is caused by enhancer hijacking resulting in MECOM overexpression. Several chromosomal rearrangements can lead to this: the most common (inv(3)/t(3;3)) results in a hijacked GATA2 enhancer, and there are several atypical MECOM rearrangements involving enhancers from other hematopoietic genes. The set of enhancers which can be hijacked by MECOM can also be hijacked by BCL11B. Enhancer deregulation is also a driver of oncogenesis in a range of other malignancies. The mechanisms of enhancer deregulation observed in other cancer types, including TAD boundary disruptions and the creation of de novo (super-) enhancers, may explain overexpression of MECOM or other oncogenes in AML without enhancer hijacking upon translocation. Gaining mechanistic insight in both enhancer deregulation and super-enhancer activity is critical to pave the way for new treatments for AML and other cancers that are the result of enhancer deregulation.
Assuntos
Elementos Facilitadores Genéticos , Leucemia Mieloide Aguda , Oncogenes , Humanos , Elementos Facilitadores Genéticos/genética , Leucemia Mieloide Aguda/genética , Oncogenes/genética , AnimaisRESUMO
Glioblastoma multiforme (GBM) is an extremely aggressive brain tumor characterized by rapid progression, poor prognosis, and limited potential for remission. A contributing factor to the aggressiveness of GBM is the high genetic and phenotypic variability of the tumor caused by the accumulation of beneficial mutations over time. Screening methodologies utilizing genetic tools such as clustered regulatory interspaced short palindromic repeats (CRISPR) and ribonucleic acid (RNA) interference (RNAi) have proven effective in identifying oncogenic driver genes in GBM. Here, we analyze and summarize these studies. Analysis of hits emerging from genetic screens in GBM has revealed key factors with the capacity for regulating deoxyribonucleic acid (DNA) repair, cell cycle, or metabolism of the cancer. The genetic programs which endow GBM a high degree of aggressiveness also contribute to outcompeting immune cells associated with tumor cell clearance. Genes identified in genetic screens influence the receptor landscape on the surface of both GBM and immune cells, as well as the soluble factors within the tumor microenvironment (TME). These soluble factors and surface receptors regulate function of immune cells, in particular natural killer (NK) cells. This systematic review links genetic drivers of GBM identified through screening approaches and their documented roles. As will be discussed, these genes were shown in literature to encode molecular programs that confer a competitive advantage to GBM in contexts such as chemotherapy and radiotherapy.
Assuntos
Neoplasias Encefálicas , Resistencia a Medicamentos Antineoplásicos , Testes Genéticos , Glioblastoma , Imunomodulação , Oncogenes , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patologia , Testes Genéticos/métodos , Glioblastoma/genética , Glioblastoma/imunologia , Imunomodulação/genética , Resistencia a Medicamentos Antineoplásicos/genética , Microambiente Tumoral , AnimaisRESUMO
This paper is intended as a contribution to the social science literature on Patient Advocacy Groups (PAGs). It examines the recent emergence and development of cancer patient organizations that self-define as "oncogene-focused," that is, as centered on tumor-driving genetic mutations that offer novel therapeutic opportunities for tumors to be targeted by precision drugs. Drawing on qualitative methods including interviews with representatives of oncogene focused PAGs, analysis of the groups' publications (biomedical journals, eNewsletters), websites, and social media activity, the paper explores the characteristics of these PAGs' forms of activism. It shows that their common denominator is a focus on patient survival. This shared goal translates into a form of activism that centers on therapeutic actionability, that is, a set of initiatives aiming at the articulation of research, clinical trials, and care to improve the patients' quality of life and maximize survival thanks to awareness of and access to the latest therapies. Beyond individual differences between PAGs, we observe the increasingly seamless entanglement of their activities. Their mutually supportive interventions result in the establishment of an ecosystemic form of activism that also succeeds in mobilizing clinicians and researchers at the increasingly porous interface between research and care.
Assuntos
Neoplasias , Oncogenes , Defesa do Paciente , Humanos , Neoplasias/genética , Neoplasias/terapia , Oncogenes/genética , Pesquisa QualitativaRESUMO
Extrachromosomal DNA (ecDNA) is a prevalent and devastating form of oncogene amplification in cancer1,2. Circular megabase-sized ecDNAs lack centromeres, stochastically segregate during cell division3-6 and persist over many generations. It has been more than 40 years since ecDNAs were first observed to hitchhike on mitotic chromosomes into daughter cell nuclei, but the mechanism underlying this process remains unclear3,7. Here we identify a family of human genomic elements, termed retention elements, that tether episomes to mitotic chromosomes to increase ecDNA transmission to daughter cells. Using Retain-seq, a genome-scale assay that we developed, we reveal thousands of human retention elements that confer generational persistence to heterologous episomes. Retention elements comprise a select set of CpG-rich gene promoters and act additively. Live-cell imaging and chromosome conformation capture show that retention elements physically interact with mitotic chromosomes at regions that are mitotically bookmarked by transcription factors and chromatin proteins. This activity intermolecularly recapitulates promoter-enhancer interactions. Multiple retention elements are co-amplified with oncogenes on individual ecDNAs in human cancers and shape their sizes and structures. CpG-rich retention elements are focally hypomethylated. Targeted cytosine methylation abrogates retention activity and leads to ecDNA loss, which suggests that methylation-sensitive interactions modulate episomal DNA retention. These results highlight the DNA elements and regulatory logic of mitotic ecDNA retention. Amplifications of retention elements promote the maintenance of oncogenic ecDNA across generations of cancer cells, and reveal the principles of episome immortality intrinsic to the human genome.
Assuntos
DNA , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/patologia , Regiões Promotoras Genéticas/genética , Mitose/genética , Ilhas de CpG/genética , Linhagem Celular Tumoral , Plasmídeos/genética , Plasmídeos/metabolismo , Genoma Humano/genética , Cromossomos Humanos/genética , Oncogenes/genética , Amplificação de Genes , Cromatina/metabolismo , DNA/genética , DNA/metabolismoRESUMO
Oral squamous cell carcinoma (OSCC) is a significant health challenge, particularly in the Indian subcontinent, where it is the second leading cause of cancer. Smoking, including waterpipe tobacco smoking, is a major risk factor for OSCC and contributes to the onset of malignancy through the absorption of carcinogenic compounds present in tobacco smoke. This study investigated the role of the oncogene Yes-associated protein 1 (YAP1) signaling pathway in OSCC progression, focusing on how exposure to waterpipe smoke condensate (WPSC) influences cellular proliferation, epithelial-mesenchymal transition (EMT), and YAP1 activity. Using immortalized human oral keratinocytes (HOK) and OSCC cell lines, we found that WPSC significantly enhanced cell proliferation, increased colony formation, and elevated YAP1 expression compared to controls. Notably, WPSC treatment resulted in the downregulation of the epithelial marker E-cadherin and the upregulation of mesenchymal markers, indicating a shift towards an invasive phenotype. Further bioinformatic analysis of The Cancer Genome Atlas (TCGA) dataset confirmed that YAP1 is frequently altered in HNSCC, highlighting its role in OSCC carcinogenesis. Our findings establish YAP1 as a central mediator in the response of oral keratinocytes to the oncogenic effects of waterpipe smoking, promoting EMT and enhancing invasive characteristics of OSCC cells. These results underscore the therapeutic potential of targeting the YAP1 signaling pathway in OSCC treatment, particularly in individuals exposed to waterpipe smoke. Future research should elucidate the molecular mechanisms of WPSC-induced YAP1 activation and EMT, paving the way for innovative therapeutic strategies to combat OSCC.
Assuntos
Carcinoma de Células Escamosas , Transição Epitelial-Mesenquimal , Neoplasias Bucais , Oncogenes , Fumaça , Fumar Cachimbo de Água , Humanos , Neoplasias Bucais/etiologia , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fumaça/efeitos adversos , Proteínas de Sinalização YAP , Proliferação de Células/efeitos dos fármacos , Fatores de Transcrição , Fumar Cachimbo de Água/efeitos adversos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/etiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Queratinócitos , Transdução de Sinais , Linhagem Celular TumoralRESUMO
Understanding how genomic variants contribute to lung cancer (LC) risk is key to better understanding the molecular mechanisms underlying that risk. While genome-wide association studies (GWAS) have identified numerous LC risk loci, most single nucleotide polymorphisms (SNPs) reside in non-coding regions, making the interpretation of their function challenging. We accounted for lung-specific chromatin interactions and allele-specific gene expression levels in lung tissue to identify novel interactions between LC GWAS SNPs and distal genes. Pathway enrichment analysis implicated eight target genes (CYP2A6, ADCY2, CHRNA3, CHRNA5, LATS1, RAD52, RIF1, TP53BP1) in functional networks involving caffeine metabolism, DNA ionizing radiation (IR)-double strand breaks and cellular response, and nicotine effect on dopaminergic neurons. Novel findings include a role for rs2853677 in ADCY2 dysregulation (previous attribution to TERT) and rs9322193 in targeting tumour suppressor gene LATS1 (previous attribution to RPS18P9/KATNA1). By linking germline variants to more biologically relevant gene targets and somatic processes, our results align more closely with established epidemiological and environmental risk factors for lung cancer, including a potential genetic explanation for the environmental interaction of caffeine and smoking in LC risk. This highlights the value of integrating 3D genome architecture and tissue-specific expression to refine our understanding of cancer susceptibility.
Assuntos
Adenilil Ciclases , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , Proteínas Serina-Treonina Quinases , Locos de Características Quantitativas , Humanos , Mutação em Linhagem Germinativa/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias Pulmonares/genética , Proteínas Serina-Treonina Quinases/genética , Adenilil Ciclases/genética , Estudo de Associação Genômica Ampla , Cafeína/efeitos adversos , Cafeína/metabolismo , Nicotina/efeitos adversos , Nicotina/metabolismo , Fatores de Risco , Predisposição Genética para Doença/genética , Oncogenes/genética , Locos de Características Quantitativas/genética , Regulação Neoplásica da Expressão Gênica/genéticaRESUMO
Long non-coding RNAs (lncRNAs) play crucial roles in regulating gene expression. Some are essential for organismal development and physiology, and they can contribute to diseases including cancer. Whilst most lncRNAs exhibit little sequence similarity, conservation of lncRNA transcription relative to neighbouring protein-coding genes suggests potential functional significance. Most positionally equivalent lncRNAs are uncharacterized and it remains unclear whether they exert similar roles in distant species. Here, we identified melanoma-associated lncRNAs predicted to be components of the MITF gene regulatory network in human melanoma that have positionally equivalent transcripts in zebrafish. We prioritized the cancer-associated lncRNA Differentiation Antagonizing Non-Protein Coding RNA (DANCR) as an exemplar for functional investigation. DANCR is a multi-exonic, cytoplasmically-enriched lncRNA and small RNA host gene transcribed from syntenic regions in the human and zebrafish genomes. MITF and c-MYC, key melanoma transcription factors, regulate human DANCR expression and melanoma patients with high DANCR display significantly decreased survival. DANCR is a melanoma oncogene that controls cancer-associated gene expression networks to promote human melanoma cell proliferation and migration. Zebrafish dancr is essential for embryonic development. It is dynamically expressed across multiple different cell types in the developing embryo, transcriptionally activated by mitfa during early zebrafish development and it regulates genes involved in cell death. Our work suggests that cancer-critical lncRNAs such as DANCR, expressed from similar regions in vertebrate genomes, may control related genes and processes involved in both embryonic development and tumorigenesis across species.
Assuntos
Melanoma , RNA Longo não Codificante , Peixe-Zebra , Animais , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/embriologia , Melanoma/genética , Melanoma/patologia , RNA Longo não Codificante/genética , Humanos , Fator de Transcrição Associado à Microftalmia/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Peixe-Zebra/genética , Proliferação de Células/genética , Regulação da Expressão Gênica no Desenvolvimento , Sintenia/genética , Desenvolvimento Embrionário/genética , Oncogenes/genética , Redes Reguladoras de Genes , Movimento Celular/genética , Proteínas Proto-Oncogênicas c-myc/genéticaRESUMO
Cyclin-dependent kinase 5 (Cdk5) is an atypical serine/threonine kinase distinct from classical cell cycle regulators. Its activity is highest in the nervous system and essential for development, but its functions in other tissues, particularly in cancer, are increasingly being elucidated. This review explores the functional duality of Cdk5 by comparing its constructive role in neurodevelopment with its repurposed oncogenic function in cancer. In neurodevelopment, Cdk5 orchestrates nearly every stage of brain construction, including neuronal differentiation, migration, and synaptic plasticity. However, in many cancers, this neurodevelopmental toolkit is repurposed, and aberrantly activated Cdk5 promotes proliferation, metastasis, and therapeutic resistance in diverse solid tumors. Cdk5 also actively shapes the tumor microenvironment by promoting angiogenesis and modulating immunity. Notably, this oncogenic function is not universal, as Cdk5 exhibits its duality even within the context of cancer; it acts as a tumor suppressor in gastric cancer upon nuclear localization. Taken together, these lines of evidence underscore that Cdk5 is a context-dependent kinase whose output is determined by upstream regulation, subcellular localization, and the cellular environment. This review discusses the molecular basis of its dual role and highlights both the potential and complexity of Cdk5 as a therapeutic target in oncology.
Assuntos
Quinase 5 Dependente de Ciclina , Neoplasias , Oncogenes , Humanos , Quinase 5 Dependente de Ciclina/metabolismo , Quinase 5 Dependente de Ciclina/genética , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismo , Neoplasias/enzimologia , Animais , Microambiente TumoralRESUMO
The Nuclear Factor I (NFI) family of transcription factors orchestrates key regulatory programs in development, differentiation, and metabolism, with dysregulation implicated in diverse pathological conditions, including cancer. Among the paralogs, NFIB has emerged as an oncogenic driver in multiple tumor types, yet the mechanisms through which it engages DNA and directs oncogenic transcriptional programs remain undefined. Here, using cancer cells with high NFIB expression, we demonstrate that NFIB promotes malignant phenotypes, as CRISPR-Cas9 knockout impairs proliferation, migration, and invasion. Transcriptomic profiling reveals that NFIB regulates a cancer-enriched gene network that includes FGFR3 and PDGFRB. Biophysical analyses show that NFIB, including its DNA-binding domain, functions as a monomer and binds DNA with strict 1:1 stoichiometry. High-resolution crystal structures of NFIB DNA-binding domain bound to ChIP-seq-derived DNA motifs reveal a monomeric binding mode mediated by conserved base-specific interactions with the TGGCA sequence, providing an atomic view of NFIB-DNA recognition. Mutational disruption of key DNA-contacting residues abolishes DNA binding and transcriptional activation, linking atomic-level recognition to oncogenic transcriptional regulation. Together, these findings elucidate the structural mechanism underlying NFIB function in cancer and establish a framework for therapeutic strategies targeting NFIB-driven malignancies.
Assuntos
Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição NFI , Neoplasias , Transcrição Gênica , Humanos , Fatores de Transcrição NFI/genética , Fatores de Transcrição NFI/química , Fatores de Transcrição NFI/metabolismo , DNA/metabolismo , DNA/química , DNA/genética , Linhagem Celular Tumoral , Sistemas CRISPR-Cas , Ligação Proteica , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismo , Proliferação de Células/genética , Oncogenes , Modelos Moleculares , Movimento Celular/genética , Ativação TranscricionalRESUMO
Stabilizing G-quadruplex structures through small molecule binding is an important area of research in cancer therapy. Cyclic AMP response element-binding protein 1 (CREB1) is a transcription factor of the CREB family that acts as an oncogene. It governs various roles in cellular processes, including the regulation of genes. CREB1 has guanine-rich regions which can form G-quadruplex (GQ) structures. Flavones are natural compounds with anticancer properties. We have investigated the binding mode and interaction mechanisms of three flavone compounds with the CREB1 GQ (CR-GQ) employing molecular docking and 100 ns molecular dynamics simulations, followed by an umbrella sampling method. The binding free energies estimated from MM-PBSA were -47.95, -107.55 and -98.28 kcal/mol, respectively, for flavone, baicalein and chrysin, showing that baicalein and chrysin bind with lower energy than flavone. Root mean square deviations and root mean square fluctuation values indicate that the GQ DNA-ligand system is stable throughout the simulations. The binding free energies and the estimated minimum values in the potential of mean force suggest that the binding reaction is energetically favourable. The compactness of the complexes is evident from the eigenvector map. Hydrogen bonds, pi-pi interactions and van der Waals interactions are the major driving forces in the complex formation. Among the three flavone compounds, baicalein and chrysin complexes are energetically more favourable than the flavone complex. The studied phytochemicals exhibit pharmacokinetic properties, suggesting their potential as promising drug candidates targeting CR-GQ. This study provides pragmatic data for discovering novel drugs targeting CR-GQ and extends the knowledge in stabilizing GQ structures using small molecules.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , DNA , Flavonas , Quadruplex G , Oncogenes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Flavonas/química , Flavonas/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/química , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Termodinâmica , Ligação Proteica , Ligação de Hidrogênio , Humanos , Sítios de Ligação , Ligantes , DNA/químicaRESUMO
Cancer genes break free from the regulatory constraints of chromosomes.
Assuntos
Cromossomos Humanos , Regulação Neoplásica da Expressão Gênica , Genes Neoplásicos , Neoplasias , Oncogenes , Animais , Humanos , Cromossomos Humanos/genética , Neoplasias/genéticaRESUMO
Over the past 2 decades, remarkable advancements in the screening, diagnosis, and treatment of non-small cell lung cancer (NSCLC) have led to improved patient outcomes. For the treatment of NSCLC with actionable gene mutations, tyrosine kinase inhibitors developed against EGFR, ALK, RET, BRAF, ROS1, NTRK, MET, and KRAS, exhibit substantial antitumor activity and have been incorporated into standard treatment regimens. Additionally, numerous novel therapies, including immunotherapy and antibody-drug conjugate therapy, have been found to benefit patients with NSCLC. This review summarizes current advancements in targeted therapy for NSCLC, according to a systematic search of the PubMed database and synthesis of cutting-edge findings presented at the 2024 American Society of Clinical Oncology Annual Meeting and 2024 World Conference on Lung Cancer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Oncogenes , Inibidores de Proteínas Quinases , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Terapia de Alvo Molecular/métodos , Mutação , Imunoterapia/métodosRESUMO
CIC::DUX4 sarcoma (CDS) is a highly aggressive malignancy with limited therapeutic options. Here, we present a doxycycline-inducible CIC::DUX4 chimeric mouse model and a cancer line derived from it, imChCDS, that faithfully recapitulates the molecular, histological, and immunological features of human CDS. We demonstrate that CIC::DUX4 expression alone is sufficient to drive tumorigenesis in permissive lineages of soft connective tissues. The imChCDS cell line retains the transcriptional footprint of its mesenchymal cell of origin, develops metastatic tumors in immunocompetent hosts, and exhibits a clear dependency on the P300/CBP transcriptional co-activators. Notably, we identify CIC::DUX4/P300/CBP-mediated suppression of MHC class I (MHCI) as a key mechanism of CDS immune evasion. Genetical inactivation of CIC::DUX4 or pharmacological inhibition of P300/CBP induces cancer cell cycle arrest, restores MHCI expression, and triggers robust anti-tumor immune responses, thereby transforming the immunologically "cold" CDS microenvironment into a "hot" one and driving tumor regression. Together, these models offer a versatile and physiologically relevant platform to investigate CDS pathogenesis, unravel immune evasion mechanisms, and evaluate emerging therapeutic strategies, including those targeting CIC::DUX4/P300/CBP oncogenic axis.
Assuntos
Proteínas de Homeodomínio , Evasão da Resposta Imune , Proteínas de Fusão Oncogênica , Oncogenes , Sarcoma , Animais , Humanos , Camundongos , Sarcoma/genética , Sarcoma/patologia , Sarcoma/imunologia , Sarcoma/metabolismo , Modelos Animais de Doenças , Linhagem Celular Tumoral , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição de p300-CBP/metabolismo , Proteínas de Fusão Oncogênica/genéticaRESUMO
Cervical cancer remains a significant global health challenge, particularly in low-income regions, where incidence and fatality rates exceed WHO eradication limits. The miRNAs are emerging as crucial molecular markers in disease diagnostics and therapeutics. Their expression is influenced by Human Papillomavirus (HPV) infection leading to genomic instability and cervical carcinogenesis. The miRNA-based biomarkers exhibit potential for noninvasive identification in serum, urine, cervical mucus, exosomes, and tissue samples, and they also contribute to chemosensitization and resistance mechanisms. However, their clinical translation is hindered by multiple challenges. This review explores the mechanistic roles of miRNAs in HPV-mediated cervical cancer progression, their implications in diagnosis and therapy, and the barriers limiting their clinical application. Additionally, it outlines strategies to overcome translational hurdles, including combinatorial delivery, structural modifications, nanovehicles based delivery, viral vector systems, paving the way for miRNA-based interventions in cervical cancer management.
Assuntos
Biomarcadores Tumorais , MicroRNAs , Oncogenes , Papillomaviridae , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/diagnóstico , MicroRNAs/genética , MicroRNAs/metabolismo , Feminino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Papillomaviridae/genéticaRESUMO
BACKGROUND: Despite the effectiveness of immune checkpoint blockade (ICB) therapy in cancer treatment, oncogene-addicted subsets of non-small cell lung cancer (NSCLC) typically derive limited benefits. Herein, we established and evaluated a mutation-based signature to predict ICB efficacy in patients with both non-mutant and oncogene-mutant NSCLC. METHODS: The predictive power of the signature was evaluated and validated across advanced NSCLCs cases with or without targetable oncogene alterations, using four public and one in-house immunotherapy cohort. NSCLC cohorts from The Cancer Genome Atlas were used to explore the underlying mechanisms of the signature. Herein, we defined a gene mutation number (GMN) based on the signature and classified patients into high and low GNM groups (GMN-H and GMN-L, respectively). RESULTS: The GMN-H group exhibited significantly improved overall survival (OS) (hazard ratio [HR], 0.23; 95% confidence interval [CI]: 0.14-0.37; P < 0.001 in the discovery cohort) and progression-free survival (HR, 0.43; 95% CI: 0.28-0.65; P < 0.001 in the discovery cohort; HR, 0.41; 95% CI: 0.26-0.66; P = 0.0011 in the validation cohort) after ICB therapy. The survival advantage of GMN-H persisted in patients with KRAS mutations, whereas only trends toward improved survival outcomes were observed in those with EGFR, HER2, or MET alterations. Moreover, in the KRASG12C- and KRASG12V-mutant subgroups, patients with GMN-H exhibited a better OS. Compared with GMN-L, GMN-H was associated with higher levels of neoantigens, enrichment of WNT and MAPK pathways, and increased intra-tumoral CD8 + T cell infiltration. CONCLUSIONS: The mutation-based signature established herein represents a robust biomarker for identifying patients with advanced NSCLCs who are most likely to benefit from ICB therapy, including those with targetable oncogene alterations.