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1.
Ann Anat ; 239: 151824, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34478856

RESUMO

BACKGROUND: Tail regeneration in lizards is the only case of large multi-tissue organ regeneration in amniotes. METHODS: The present Review summarizes numerous immunolocalization and gene-expression studies indicating that after tail amputation in lizards the stump is covered in 7-10 days by the migration of keratinocytes. This allows the accumulation of mesenchymal-fibroblasts underneath the wound epidermis and forms a regenerative blastema and a new tail. RESULTS: During migration keratinocytes transit from a compact epidermis into relatively free keratinocytes in a process of "Epithelial Mesenchymal Transition" (EMT). While EMT has been implicated in carcinogenesis no malignant transformation is observed during these cell movements in the regenerative blastema. Immunolabeling for E-cadherin and snail shows that these proteins are present in the cytoplasm and nuclei of migrating keratinocytes. The basal layer of the wound epithelium of the apical blastema express onco-proteins (wnt2b, egfr, c-myc, fgfs, fgfr, rhov, etc.) and tumor suppressors (p53/63, fat2, ephr, apc, retinoblastoma, arhgap28 etc.). This suggests that their balanced action regulates proliferation of the blastema. CONCLUSIONS: While apical epidermis and mesenchyme are kept under a tight proliferative control, in more proximal regions of the regenerating tail the expression of tumor-suppressors triggers the differentiation of numerous tissues, forming the large myomeres, axial cartilage, simple spinal cord and nerves, new scales, arteries and veins, fat deposits, dermis and other connective tissues. Understanding gene expression patterns of developmental pathways activated during tail regeneration in lizards is useful for cancer research and for future attempts to induce organ regeneration in other amniotes including humans.


Assuntos
Lagartos , Animais , Diferenciação Celular , Derme , Epiderme , Proteínas de Ligação ao GTP , Humanos , Proteínas de Neoplasias , Oncogenes , Cauda
2.
BMC Bioinformatics ; 22(1): 537, 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34727887

RESUMO

BACKGROUND: Identification of molecular mechanisms that determine tumour progression in cancer patients is a prerequisite for developing new disease treatment guidelines. Even though the predictive performance of current machine learning models is promising, extracting significant and meaningful knowledge from the data simultaneously during the learning process is a difficult task considering the high-dimensional and highly correlated nature of genomic datasets. Thus, there is a need for models that not only predict tumour volume from gene expression data of patients but also use prior information coming from pathway/gene sets during the learning process, to distinguish molecular mechanisms which play crucial role in tumour progression and therefore, disease prognosis. RESULTS: In this study, instead of initially choosing several pathways/gene sets from an available set and training a model on this previously chosen subset of genomic features, we built a novel machine learning algorithm, PrognosiT, that accomplishes both tasks together. We tested our algorithm on thyroid carcinoma patients using gene expression profiles and cancer-specific pathways/gene sets. Predictive performance of our novel multiple kernel learning algorithm (PrognosiT) was comparable or even better than random forest (RF) and support vector regression (SVR). It is also notable that, to predict tumour volume, PrognosiT used gene expression features less than one-tenth of what RF and SVR algorithms used. CONCLUSIONS: PrognosiT was able to obtain comparable or even better predictive performance than SVR and RF. Moreover, we demonstrated that during the learning process, our algorithm managed to extract relevant and meaningful pathway/gene sets information related to the studied cancer type, which provides insights about its progression and aggressiveness. We also compared gene expressions of the selected genes by our algorithm in tumour and normal tissues, and we then discussed up- and down-regulated genes selected by our algorithm while learning, which could be beneficial for determining new biomarkers.


Assuntos
Aprendizado de Máquina , Neoplasias , Algoritmos , Humanos , Neoplasias/genética , Oncogenes , Carga Tumoral
4.
BMC Genomics ; 22(1): 833, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34789165

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer. Approximately 80% of patients initially diagnosed with locally advanced or metastatic disease survive only 4-11 months after diagnosis. Tremendous efforts have been made toward understanding the biology of PDAC. RESULTS: In this study, we first utilized next-generation sequencing technique and existing microarray datasets to identify significant differentially expressed genes between PDAC and non-tumor adjacent tissue. By comparing top significant survival genes in PDAC Gene Expression Profiling Interactive Analysis database and PDAC transcriptome data from patients, our integrated analysis discovered five potential central genes (i.e., MYEOV, KCNN4, FAM83A, S100A16, and DDX60L). Subsequently, we analyzed the cellular functions of the potential novel oncogenes MYEOV and DDX60L, which are highly expressed in PDAC cells. Notably, the knockdown of MYEOV and DDX60L significantly inhibited the metastasis of cancer cells and induced apoptosis. Further RNA sequencing analyses showed that massive signaling pathways, particularly the TNF signaling pathway and nuclear factor-kappa B (NF-κB) signaling pathway, were affected in siRNA-treated cancer cells. The siDDX60L and siMYEOV significantly inhibited the expression of chemokine CXCL2, which may potentially affect the tumor microenvironment in PDAC tissues. CONCLUSIONS: The present findings identified the novel oncogene DDX60L, which was highly expressed in PDAC. Transcriptome profiling through siRNA knockdown of DDX60L uncovered its functional roles in the PDAC in humans.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Biomarcadores Tumorais , Carcinoma Ductal Pancreático/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Neoplasias , Oncogenes , Neoplasias Pancreáticas/genética , Microambiente Tumoral
5.
World J Gastroenterol ; 27(38): 6387-6398, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34720529

RESUMO

Specificity protein (Sp) transcription factors (TFs) Sp1, Sp3 and Sp4, and the orphan nuclear receptor 4A1 (NR4A1) are highly expressed in pancreatic tumors and Sp1 is a negative prognostic factor for pancreatic cancer patient survival. Results of knockdown and overexpression of Sp1, Sp3 and Sp4 in pancreatic and other cancer lines show that these TFs are individually pro-oncogenic factors and loss of one Sp TF is not compensated by other members. NR4A1 is also a pro-oncogenic factor and both NR4A1 and Sp TFs exhibit similar functions in pancreatic cancer cells and regulate cell growth, survival, migration and invasion. There is also evidence that Sp TFs and NR4A1 regulate some of the same genes including survivin, epidermal growth factor receptor, PAX3-FOXO1, α5- and α6-integrins, ß1-, ß3- and ß4-integrins; this is due to NR4A1 acting as a cofactor and mediating NR4A1/Sp1/4-regulated gene expression through GC-rich gene promoter sites. Several studies show that drugs targeting Sp downregulation or NR4A1 antagonists are highly effective inhibitors of Sp/NR4A1-regulated pathways and genes in pancreatic and other cancer cells, and the triterpenoid celastrol is a novel dual-acting agent that targets both Sp TFs and NR4A1.


Assuntos
Neoplasias Pancreáticas , Fatores de Transcrição , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Oncogenes , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Receptores Citoplasmáticos e Nucleares/genética , Fatores de Transcrição Sp/genética , Fatores de Transcrição Sp/metabolismo , Fatores de Transcrição/genética
6.
Lung Cancer ; 161: 163-170, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34600407

RESUMO

OBJECTIVES: Programmed death-ligand 1 (PD-L1) expression is a predictive biomarker of response to immunotherapies targeting programmed death-1/PD-L1 in advanced-stage lung adenocarcinoma. The aim of this study was to investigate the associations between PD-L1 expression and clinicopathological features, prognosis, and driver oncogene alterations in patients with lung adenocarcinoma. MATERIALS AND METHODS: We evaluated PD-L1 expression in 1,005 surgically resected lung adenocarcinoma specimens, by immunohistochemistry using the 22C3 antibody. PD-L1 positivity was defined based on the proportion of stained tumor cells (TPS) on tissue microarrays: <1% (negative), 1-49% (weakly positive), and ≥ 50% (strongly positive). Correlations between PD-L1 expression and clinicopathological features, prognosis, and driver oncogene (EGFR, KRAS, ALK, ROS1, and RET) alterations in lung adenocarcinoma were analyzed. RESULTS: PD-L1 expression was negative in 726 (72%) of 1,005 tumors, weakly positive in 161 (16%), and strongly positive in 118 (12%). Male sex, smoking, elevated serum carcinoembryonic antigen levels, advanced pathological stages, high-grade tumors, predominantly solid tumors, tumors with lymphatic permeation or vascular or pleural invasion, tumors without EGFR mutations, and tumors with KRAS mutations were more common in patients with PD-L1-positive tumors (TPS ≥ 1%) than in those with PD-L1-negative tumors (TPS < 1%). PD-L1 positivity was not associated with ALK, ROS1, or RET fusion status. Although PD-L1 positivity was associated with poor overall survival and poor relapse-free survival in all patients, this was not statistically significant after adjusting for prognostic factors in the multivariate analysis. In the subgroup analysis according to driver oncogene alterations, PD-L1 positivity was associated with poor relapse-free survival only in patients with EGFR-mutated tumors. CONCLUSION: Surgically resected lung adenocarcinomas with increased PD-L1 expression were biologically aggressive tumors that frequently occurred in male smokers. PD-L1 expression and its prognostic significance differed according to driver oncogene alterations.


Assuntos
Adenocarcinoma de Pulmão , Antígeno B7-H1/metabolismo , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Quinase do Linfoma Anaplásico/genética , Antígeno B7-H1/genética , Biomarcadores Tumorais , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirurgia , Masculino , Recidiva Local de Neoplasia , Oncogenes , Prognóstico , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética
7.
BMC Bioinformatics ; 22(Suppl 4): 491, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34689757

RESUMO

BACKGROUND: Genetic information is becoming more readily available and is increasingly being used to predict patient cancer types as well as their subtypes. Most classification methods thus far utilize somatic mutations as independent features for classification and are limited by study power. We aim to develop a novel method to effectively explore the landscape of genetic variants, including germline variants, and small insertions and deletions for cancer type prediction. RESULTS: We proposed DeepCues, a deep learning model that utilizes convolutional neural networks to unbiasedly derive features from raw cancer DNA sequencing data for disease classification and relevant gene discovery. Using raw whole-exome sequencing as features, germline variants and somatic mutations, including insertions and deletions, were interactively amalgamated for feature generation and cancer prediction. We applied DeepCues to a dataset from TCGA to classify seven different types of major cancers and obtained an overall accuracy of 77.6%. We compared DeepCues to conventional methods and demonstrated a significant overall improvement (p < 0.001). Strikingly, using DeepCues, the top 20 breast cancer relevant genes we have identified, had a 40% overlap with the top 20 known breast cancer driver genes. CONCLUSION: Our results support DeepCues as a novel method to improve the representational resolution of DNA sequencings and its power in deriving features from raw sequences for cancer type prediction, as well as discovering new cancer relevant genes.


Assuntos
Aprendizado Profundo , Neoplasias , Humanos , Neoplasias/genética , Oncogenes , Análise de Sequência de DNA , Sequenciamento Completo do Exoma
8.
Nat Commun ; 12(1): 5906, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625563

RESUMO

Mouse models are critical in pre-clinical studies of cancer therapy, allowing dissection of mechanisms through chemical and genetic manipulations that are not feasible in the clinical setting. In studies of the tumour microenvironment (TME), multiplexed imaging methods can provide a rich source of information. However, the application of such technologies in mouse tissues is still in its infancy. Here we present a workflow for studying the TME using imaging mass cytometry with a panel of 27 antibodies on frozen mouse tissues. We optimise and validate image segmentation strategies and automate the process in a Nextflow-based pipeline (imcyto) that is scalable and portable, allowing for parallelised segmentation of large multi-image datasets. With these methods we interrogate the remodelling of the TME induced by a KRAS G12C inhibitor in an immune competent mouse orthotopic lung cancer model, highlighting the infiltration and activation of antigen presenting cells and effector cells.


Assuntos
Citometria por Imagem/métodos , Oncogenes , Microambiente Tumoral/imunologia , Animais , Anticorpos , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/imunologia , Modelos Animais de Doenças , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Oncogenes/efeitos dos fármacos , Linfócitos T , Microambiente Tumoral/efeitos dos fármacos
9.
Mol Cell ; 81(18): 3672-3674, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34547231

RESUMO

Igelmann et al. report a novel metabolic cycle, which they name HTC, that converts NADH into the key antioxidant factor NADPH. The HTC is repressed by the tumor suppressors p53 and RB, and this determines whether oncogene-expressing cells undergo senescence (HTCoff) or malignant transformation (HTCon).


Assuntos
Senescência Celular , Neoplasias , Senescência Celular/genética , Humanos , Neoplasias/genética , Oncogenes/genética , Oxirredução , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
10.
Science ; 373(6559): 1088-1089, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34516853

RESUMO

[Figure: see text].


Assuntos
Oncogenes
11.
Zhonghua Zhong Liu Za Zhi ; 43(9): 901-905, 2021 Sep 23.
Artigo em Chinês | MEDLINE | ID: mdl-34530570

RESUMO

Breast cancer is one of the common malignant tumors of women. In recent years, the incidence of breast cancer is high. Human epidermal growth factor receptor-2 (HER-2) is a tyrosine kinase receptor. Breast cancer with abnormal amplification or overexpression of HER-2 have the characteristics of strong tumor invasiveness and poor prognosis. With the advent of anti-HER-2 drugs, the survival period of patients with HER-2 positive breast cancer is gradually prolonged, and the prognosis of patients with HER-2 positive breast cancer is improved. However, the efficacy of traditional HER-2 targeted drugs on patients with low expression of HER-2 is very limited, and the treatment of breast cancer with low expression of HER-2 is still facing challenges. This article reviews the standardization process of the American Society of Clinical Oncology and the American Society of Pathologists guidelines for HER-2 detection, and puts forward the data basis and possibility of defining a new subtype of breast cancer with low expression of HER-2. The birth of a new generation of HER-2 targeting drugs makes it possible to treat patients with low expression of HER-2, which will redefine breast cancer with low expression of HER-2 and provide a new opportunity for the prognosis of patients with low expression of HER-2.


Assuntos
Antineoplásicos , Neoplasias da Mama , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Humanos , Oncogenes , Prognóstico
12.
Front Cell Infect Microbiol ; 11: 704100, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34513727

RESUMO

Objective: To investigate variation in gut microbiome in female patients with invasive mole (IM) and choriocarcinoma (CC) and compare it with healthy controls. Methods: Fecal microbiome of 12 female patients with IM, 9 female patients with CC, and 24 healthy females were analyzed based on 16s rDNA sequencing. Alpha (α) diversity was evaluated using Shannon diversity index and Pielou evenness index, while beta (ß) diversity was assessed using principle coordinate analysis (PCoA) of unweighted Unifrac distances. The potential functional changes of microbiomes were predicted using Tax4Fun. The relative abundance of microbial taxa was compared using Welch's t test. The role of varied gut microbiota was analyzed via receiver operating characteristic (ROC) curve. Results: The α diversity and ß diversity were significantly different between IM patients and controls, but not between CC patients and controls. In addition, the abundance of cancer-related genes was significantly increased in IM and CC patients. Notably, a total of 19 families and 39 genera were found to have significant differences in bacterial abundance. ROC analysis indicated that Prevotella_7 may be a potential biomarker among IM, CC, and controls. Conclusion: Our study demonstrated that the diversity and composition of gut microbiota among IM patients, CC patients, and healthy females were significantly different, which provides rationale for using gut microbiota as diagnostic markers and treatment targets, as well as for further study of gut microbiota in gestational trophoblastic neoplasia (GTN).


Assuntos
Coriocarcinoma , Microbioma Gastrointestinal , Mola Hidatiforme Invasiva , Neoplasias Uterinas , Fezes , Feminino , Humanos , Oncogenes , Gravidez , RNA Ribossômico 16S/genética
13.
Nat Commun ; 12(1): 5574, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34552099

RESUMO

In a trial of patients with high grade serous ovarian cancer (HGSOC), addition of the ATR inhibitor berzosertib to gemcitabine improved progression free survival (PFS) compared to gemcitabine alone but biomarkers predictive of treatment are lacking. Here we report a candidate biomarker of response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in HGSOC ovarian cancer. Patients with replication stress (RS)-high tumors (n = 27), defined as harboring at least one genomic RS alteration related to loss of RB pathway regulation and/or oncogene-induced replication stress achieve significantly prolonged PFS (HR = 0.38, 90% CI, 0.17-0.86) on gemcitabine monotherapy compared to those with tumors without such alterations (defined as RS-low, n = 30). However, addition of berzosertib to gemcitabine benefits only patients with RS-low tumors (gemcitabine/berzosertib HR 0.34, 90% CI, 0.13-0.86) and not patients with RS-high tumors (HR 1.11, 90% CI, 0.47-2.62). Our findings support the notion that the exacerbation of RS by gemcitabine monotherapy is adequate for lethality in RS-high tumors. Conversely, for RS-low tumors addition of berzosertib-mediated ATR inhibition to gemcitabine is necessary for lethality to occur. Independent prospective validation of this biomarker is required.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Replicação do DNA/genética , Desoxicitidina/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Biomarcadores Tumorais/genética , Desoxicitidina/uso terapêutico , Feminino , Humanos , Isoxazóis/uso terapêutico , Mutação , Oncogenes/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Intervalo Livre de Progressão , Pirazinas/uso terapêutico , Reparo de DNA por Recombinação/genética , Proteínas de Ligação a Retinoblastoma/genética
14.
Crit Rev Oncol Hematol ; 166: 103477, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34534658

RESUMO

Cancer can be caused by various factors, including the malfunction of tumor suppressor genes and the hyper-activation of proto-oncogenes. Tumor-associated extrachromosomal circular DNA (eccDNA) has been shown to adversely affect human health and accelerate malignant actions. Whole-genome sequencing (WGS) on different cancer types suggested that the amplification of ecDNA has increased the oncogene copy number in various cancers. The unique structure and function of ecDNA, its profound significance in cancer, and its help in the comprehension of current cancer genome maps, renders it as a hotspot to explore the tumor pathogenesis and evolution. Illumination of the basic mechanisms of ecDNA may provide more insights into cancer therapeutics. Despite the recent advances, different features of ecDNA require further elucidation. In the present review, we primarily discussed the characteristics, biogenesis, genesis, and origin of ecDNA and later highlighted its functions in both tumorigenesis and therapeutic resistance of different cancers.


Assuntos
DNA Circular/genética , DNA de Neoplasias/genética , Neoplasias , Oncogenes , Carcinogênese , Humanos , Neoplasias/genética
16.
Cancer Treat Rev ; 100: 102291, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34587557

RESUMO

Non-small cell lung cancer (NSCLC) with oncogenic driver mutations such as EGFR or ALK has a high predilection for brain metastases (BMs) compared to unselected patients. Historically, whole brain radiotherapy (WBRT) was adopted widely for patients with BM. More recently, stereotactic radiosurgery (SRS) has become a standard approach for patients with 1 - 4 metastatic brain lesions. However, data on overall survival benefit with WBRT/SRS compared to target agents are conflicting, with a significant compromise of loss of neurocognitive function. Newer target agents with improved CNS efficacy have challenged the use of early radiotherapy in NSCLC patients with oncogenic driver mutations. Optimal treatment approach and timing of radiotherapy remain unclear, especially under the various clinical contexts. The purpose of this review is to summarize the available data on the possible benefits and risks of early radiotherapy for oncogenic-driven NSCLC patients with brain metastases. Clinical decisions should consider both intracranial efficacy and patient quality of life, given that patients are surviving long enough to experience the long-term consequences of radiation therapy.


Assuntos
Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/secundário , Neoplasias Encefálicas/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Irradiação Craniana/métodos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Oncogenes , Radiocirurgia/métodos
17.
Nat Commun ; 12(1): 5505, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535668

RESUMO

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients.


Assuntos
Proteína DEAD-box 58/metabolismo , Imunidade Inata , Inflamação/patologia , Sistema de Sinalização das MAP Quinases , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptores Imunológicos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citocinas/metabolismo , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Evasão da Resposta Imune/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Fator Regulador 1 de Interferon/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Oncogenes , Transdução de Sinais/efeitos dos fármacos
18.
Int J Mol Sci ; 22(18)2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34575830

RESUMO

In principle, an oncogene is a cellular gene (proto-oncogene) that is dysfunctional, due to mutation and fusion with another gene or overexpression. Generally, oncogenes are viewed as deregulating cell proliferation or suppressing apoptosis in driving cancer. The cancer stem cell theory states that most, if not all, cancers are a hierarchy of cells that arises from a transformed tissue-specific stem cell. These normal counterparts generate various cell types of a tissue, which adds a new dimension to how oncogenes might lead to the anarchic behavior of cancer cells. It is that stem cells, such as hematopoietic stem cells, replenish mature cell types to meet the demands of an organism. Some oncogenes appear to deregulate this homeostatic process by restricting leukemia stem cells to a single cell lineage. This review examines whether cancer is a legacy of stem cells that lose their inherent versatility, the extent that proto-oncogenes play a role in cell lineage determination, and the role that epigenetic events play in regulating cell fate and tumorigenesis.


Assuntos
Linhagem da Célula/genética , Regulação Neoplásica da Expressão Gênica , Células-Tronco Neoplásicas/metabolismo , Oncogenes , Proto-Oncogenes , Animais , Biomarcadores Tumorais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Epigênese Genética , Humanos , Células-Tronco Neoplásicas/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo
19.
Sci Rep ; 11(1): 17471, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471161

RESUMO

P21-activated kinases (PAKs) are serine/threonine protein kinase which have six different isoforms (PAK1-6). Of those, PAK1 is overexpressed in many cancers and considered to be a major chemotherapeutic target. Most of the developed PAK1 inhibitor drugs work as pan-PAK inhibitors and show undesirable toxicity due to having untargeted kinase inhibition activities. Selective PAK1 inhibitors are therefore highly desired and oncogenic drug hunters are trying to develop allosteric PAK1 inhibitors. We previously synthesized 1,2,3-triazolyl ester of ketorolac (15K) through click chemistry technique, which exhibits significant anti-cancer effects via inhibiting PAK1. Based on the selective anticancer effects of 15K against PAK1-dependent cancer cells, we hypothesize that it may act as an allosteric PAK1 inhibitor. In this study, computational analysis was done with 15K to explore its quantum chemical and thermodynamic properties, molecular interactions and binding stability with PAK1, physicochemical properties, ADMET, bioactivities, and druglikeness features. Molecular docking analysis demonstrates 15K as a potent allosteric ligand that strongly binds to a novel allosteric site of PAK1 (binding energy ranges - 8.6 to - 9.2 kcal/mol) and does not target other PAK isoforms; even 15K shows better interactions than another synthesized PAK1 inhibitor. Molecular dynamics simulation clearly supports the stable binding properties of 15K with PAK1 crystal. Density functional theory-based calculations reveal that it can be an active drug with high softness and moderate polarity, and ADMET predictions categorize it as a non-toxic drug as evidenced by in vitro studies with brine shrimp and fibroblast cells. Structure-activity relationship clarifies the role of ester bond and triazol moiety of 15K in establishing novel allosteric interactions. Our results summarize that 15K selectively inhibits PAK1 as an allosteric inhibitor and in turn shows anticancer effects without toxicity.


Assuntos
Ésteres/química , Cetorolaco/metabolismo , Modelos Moleculares , Oncogenes , Triazóis/química , Quinases Ativadas por p21/química , Quinases Ativadas por p21/metabolismo , Células 3T3 , Regulação Alostérica , Animais , Cetorolaco/química , Camundongos , Simulação de Dinâmica Molecular , Conformação Proteica
20.
Helicobacter ; 26(6): e12849, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34490965

RESUMO

BACKGROUND: Activin A receptor type I (ACVR1) is involved in tumorigenesis. However, the underlying molecular mechanisms of ACVR1 in gastric cancer (GC) and its association with Helicobacter pylori remained unclear. MATERIALS AND METHODS: The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) database were utilized to explore the ACVR1 expression in GC and normal control and its association with survival. The ACVR1 was knocked out using CRISPR/Cas-9; RNA sequencing analysis was performed in AGS cells with ACVR1 knockout and normal control. Functional experiments (CCK-8, colony-forming, and transwell assays) were conducted to demonstrate the role of ACVR1 in cell proliferation, invasion, and metastasis. H. pylori-infected C57/BL6 models were established. ACVR1, p-Smad1/5, and CDX2 were detected in AGS cells cocultured with H. pylori strains. The CDX2 and key elements of BMP signaling pathway were detected in AGS cells with ACVR1 knockout and normal control. In addition, Immunohistochemistry was performed to detect the ACVR1 and CDX2 expression in gastric samples. RESULTS: ACVR1 expression was higher in GC than normal control from TCGA, GEPIA, and samples collected from our hospital (p < 0.05). ACVR1 promoted cell proliferation, migration, and invasion in vitro. Both cagA+ and cagA- H. pylori could upregulate the expression ACVR1 (p < 0.05). Downregulation of ACVR1 inhibited the H. pylori-induced cell proliferation, migration, and invasion (p < 0.05). H. pylori increased the expression of p-Smad 1/5 and CDX2. The CDX2 and key elements of BMP signaling pathway were downregulated in AGS cells with ACVR1 knockout. ACVR1 and CDX2 were upregulated in the stage of intestinal metaplasia (IM). Moreover, ACVR1 and CDX2 expressions were higher in H. pylori-positive group than H. pylori-negative group (p < 0.05). CONCLUSION: Our data indicate that H. pylori infection increases ACVR1 expression, promoting gastric IM via regulating CDX2, which is an essential step in H. pylori carcinogenesis.


Assuntos
Receptores de Ativinas Tipo I , Fator de Transcrição CDX2 , Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Ativinas , Animais , Fator de Transcrição CDX2/genética , Fator de Transcrição CDX2/metabolismo , Mucosa Gástrica/metabolismo , Helicobacter pylori/genética , Helicobacter pylori/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Metaplasia , Camundongos , Camundongos Endogâmicos C57BL , Oncogenes , Neoplasias Gástricas/genética , Regulação para Cima
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