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1.
Cell Death Dis ; 12(7): 669, 2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34218261

RESUMO

Malignant transformation of gastrointestinal stromal tumors (GISTs) is correlated with poor prognosis; however, the underlying biological mechanism is not well understood. In the present study, low-risk (LR) GISTs, GISTs categorized as high-risk based on tumor size (HBS), and on mitotic rate (HBM) were collected for RNA sequencing. Candidate hub lncRNAs were selected by Oncomine analysis. Expression of a selected hub lncRNA, DNM3OS, and its correlation with patients' prognosis were analyzed using FISH staining, followed with the determination of function and underlying mechanism. Our results revealed a series of key pathways and hub lncRNAs involved in the malignant transformation of GISTs. Oncomine analysis revealed a tight association between clinical signatures and DNM3OS and suggested that DNM3OS is a hub lncRNA that is involved in the Hippo signaling pathway. In addition, DNM3OS was upregulated in HBS, HBM, and HBS/M GIST and correlated with worse prognosis in patients with GISTs. In addition, DNM3OS promoted GIST cell proliferation and mitosis by regulating the expression of GLUT4 and CD36. Collectively, these results improve our understanding of the malignant transformation of GISTs and unveil a series of hub lncRNAs in GISTs.


Assuntos
Transformação Celular Neoplásica/genética , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/genética , Perfilação da Expressão Gênica , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Transcriptoma , Antígenos CD36/genética , Antígenos CD36/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Bases de Dados Genéticas , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/patologia , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Humanos , Mitose , Mapas de Interação de Proteínas , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais
3.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200790

RESUMO

Exosomes released from tumor cells are instrumental in shaping the local tumor microenvironment to allow cancer progression. Recently, it has been shown that tumor exosomes carry large fragments of dsDNA, which may reflect the mutational status of parental cells. Although it has been described that a stressful microenvironment can influence exosomal cargo, the effects on DNA packing and its transfer into recipient cells have yet to be investigated. Here, we report that exosomes derived from SW480 (human colorectal adenocarcinoma cell line) cells can carry dsDNA fragments containing the entire coding sequence of both TP53 and KRAS genes, harboring the SW480-related TP53 c.818G > A and KRAS c.35G > T typical mutations. We also report the following: that cell stimulation with lipopolysaccharides (LPS) promotes the selective packaging of the TP53 gene, but not the KRAS gene; that exosomes secreted by SW480 cells efficiently transfer the mutated sequences into normal CCD841-CoN colon epithelial and THLE-2 hepatic cells; that this mechanism is more efficient when the cells had been previously incubated with pro-inflammatory cytokines; that the TP53 gene appears actively transcribed in both recipient cells; and that mutated mRNA levels are not influenced by cytokine treatment. Our data strongly suggest that pro-inflammatory stimulation promotes the horizontal transfer of an oncogene by exosomes, although this remains a rare event. Further studies are needed to assess the impact of the oncogenic transfer by exosomes in malignant transformation and its role in tumor progression.


Assuntos
Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/patologia , Exossomos/genética , Mediadores da Inflamação/imunologia , Mutação , Microambiente Tumoral/imunologia , Proteína Supressora de Tumor p53/genética , Transformação Celular Neoplásica/genética , Neoplasias Colorretais/genética , Humanos , Células Tumorais Cultivadas
4.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188576, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34090932

RESUMO

Hematopoietic PBX interacting protein (HPIP or pre-B-cell leukemia transcription factor interacting protein (PBXIP1) was discovered two decades ago as a corepressor of pre-B-cell leukemia homeobox (PBX) 1 with a vital functional role in hematopoiesis. Later it emerged as a potential biomarker of poor prognosis and tumorigenesis for more than a dozen different cancers. It regulates aggressive cancer phenotypes, cell proliferation, metastasis, EMT, etc. The anomaly in the regulation of HPIP is linked with physiological disorders like renal fibrosis, chronic kidney disease and osteoarthritis. Scientists have unraveled more than twenty interacting proteins of HPIP and its functional role in various physiological and cellular processes that involves normal neuronal development, embryogenesis, endometrium decidualization, and germ cell proliferation. Over the past 20 years, we have witnessed the emerging role of HPIP and its association with a myriad of cellular activities ranging from germ cell proliferation to cancer aggressiveness, modulating multitude of signaling cascades like TGF-ß1, PI3K/AKT, Wnt, mTOR, and Sonic hedgehog signaling pathways. This review will give the current understanding of HPIP, in terms of its diverse functions, theoretical ideas, and further explore cellular links and promising areas that need to be investigated. We also provide a comprehensive overview of the transcript variants of HPIP and distinct sets of transcription factors regulating their expression, which may help to understand the role of HPIP in various cellular or physiological conditions.


Assuntos
Transformação Celular Neoplásica/metabolismo , Proteínas Correpressoras/metabolismo , Células Germinativas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Sítios de Ligação , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Proteínas Correpressoras/genética , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Invasividade Neoplásica , Neoplasias/genética , Neoplasias/patologia , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais
5.
J Cancer Res Clin Oncol ; 147(8): 2199-2207, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34115239

RESUMO

Colorectal cancer is an important public health concern leading to significant cancer associate mortality. A vast majority of colon cancer arises from polyp which later follows adenoma, adenocarcinoma, and carcinoma sequence. This whole process takes several years to complete and recent genomic and proteomic technologies are identifying several targets involved in each step of polyp to carcinoma transformation in a large number of studies. Current text presents interaction network of targets involved in polyp to carcinoma transformation. In addition, important targets involved in each step according to network biological parameters are also presented. The functional overrepresentation analysis of each step targets and common top biological processes and pathways involved in carcinoma indicate several insights about this whole mechanism. Interaction networks indicate TP53, AKT1, GAPDH, INS, EGFR, and ALB as the most important targets commonly involved in polyp to carcinoma sequence. Though several important pathways are known to be involved in CRC, the central common involvement of PI3K-AKT indicates its potential for devising CRC management strategies. The common and central targets and pathways involved in polyp to carcinoma progression can shed light on its mechanism and potential management strategies. The data-driven approach aims to add valuable inputs to the mechanism of the years-long polyp-carcinoma sequence.


Assuntos
Carcinoma/prevenção & controle , Transformação Celular Neoplásica , Neoplasias do Colo/prevenção & controle , Pólipos do Colo/terapia , Terapia de Alvo Molecular/métodos , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/prevenção & controle , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Adenoma/prevenção & controle , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/metabolismo , Pólipos Adenomatosos/patologia , Pólipos Adenomatosos/prevenção & controle , Antineoplásicos/uso terapêutico , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Pólipos do Colo/genética , Pólipos do Colo/metabolismo , Pólipos do Colo/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/fisiologia , Genes de Troca/efeitos dos fármacos , Humanos , Mapas de Interação de Proteínas/efeitos dos fármacos , Mapas de Interação de Proteínas/genética , Proteômica , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
7.
Acta Cytol ; 65(5): 403-410, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34120116

RESUMO

INTRODUCTION: Tobacco contains several genotoxic agents including N-nitrosamine which has the potential to cause significant nuclear damage. Nuclear blebbing is a form of protrusion on the nuclear membrane and could potentially be caused by tobacco-induced genotoxicity and is closely associated with malignancy. Thus, the present study aimed to assess if tobacco-associated oral potentially malignant disorders including oral submucous fibrosis (OSF) and oral leukoplakia have a higher nuclear blebbing frequency than patients with normal oral mucosa with no history of tobacco use. METHODS: The sample consisted of patients with OSF (n = 30) and oral leukoplakia (n = 10) and normal oral mucosa (n = 10). Exfoliated cells collected from the study groups were smeared on a clean microscopic slide and stained by May-Grunwald-Giemsa stain. A baseline frequency of nuclear blebbing was evaluated using a bright-field microscope with a ×100 objective. The number of nuclear blebbing per 1,000 epithelial cells was recorded and expressed in percentage. ANOVA, the Mann-Whitney U test, and Spearman's correlation were used to analyze the data. RESULTS: The mean rank of distribution of nuclear blebbing showed significant difference between all 3 groups, with the highest frequency noted in leukoplakia, followed by oral submucous and normal oral mucosa. Within OSF, the frequency of nuclear blebbing significantly increased from early stage to advanced stage. In OSF, a statistically significant positive linear correlation was noted between duration (in years), frequency (per day) of tobacco use, clinical grading, and nuclear blebbing. DISCUSSION/CONCLUSIONS: The frequency of nuclear blebbing was significantly higher in oral potentially malignant disorders than normal mucosa. Nuclear blebbing also exhibited a strong dose- and time-dependent correlation with tobacco usage and clinical staging in OSF. The nuclear blebbing frequency could be a noninvasive, economic tool to assess malignant risk in tobacco-induced oral potentially malignant disorders.


Assuntos
Transformação Celular Neoplásica/patologia , Mucosa Bucal/patologia , Neoplasias Bucais/etiologia , Fibrose Oral Submucosa/etiologia , Uso de Tabaco/efeitos adversos , Adulto , Núcleo Celular/patologia , Humanos , Leucoplasia Oral/patologia , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Fibrose Oral Submucosa/patologia , Tabaco
8.
Int J Mol Sci ; 22(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066491

RESUMO

Poor efficiency of chemotherapeutics in the eradication of Cancer Stem Cells (CSCs) has been driving the search for more active and specific compounds. In this work, we show how cell density-dependent stage culture profiles can be used in drug development workflows to achieve more robust drug activity (IC50 and EC50) results. Using flow cytometry and light microscopy, we characterized the cytological stage profiles of the HL-60-, A-549-, and HEK-293-derived sublines with a focus on their primitive cell content. We then used a range of cytotoxic substances-C-123, bortezomib, idarubicin, C-1305, doxorubicin, DMSO, and ethanol-to highlight typical density-related issues accompanying drug activity determination. We also showed that drug EC50 and selectivity indices normalized to primitive cell content are more accurate activity measurements. We tested our approach by calculating the corrected selectivity index of a novel chemotherapeutic candidate, C-123. Overall, our study highlights the usefulness of accounting for primitive cell fractions in the assessment of drug efficiency.


Assuntos
Antineoplásicos/farmacologia , Contagem de Células , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/patologia , Humanos , Concentração Inibidora 50 , Estadiamento de Neoplasias , Espécies Reativas de Oxigênio/metabolismo
9.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070384

RESUMO

Over the last decades, the study of cancer metabolism has returned to the forefront of cancer research and challenged the role of genetics in the understanding of cancer development. One of the major impulses of this new trend came from the discovery of oncometabolites, metabolic intermediates whose abnormal cellular accumulation triggers oncogenic signalling and tumorigenesis. These findings have led to reconsideration and support for the long-forgotten hypothesis of Warburg of altered metabolism as oncogenic driver of cancer and started a novel paradigm whereby mitochondrial metabolites play a pivotal role in malignant transformation. In this review, we describe the evolution of the cancer metabolism research from a historical perspective up to the oncometabolites discovery that spawned the new vision of cancer as a metabolic disease. The oncometabolites' mechanisms of cellular transformation and their contribution to the development of new targeted cancer therapies together with their drawbacks are further reviewed and discussed.


Assuntos
Transformação Celular Neoplásica/metabolismo , Doenças Metabólicas/metabolismo , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Transdução de Sinais , Transformação Celular Neoplásica/patologia , Humanos , Doenças Metabólicas/patologia , Mitocôndrias/patologia , Neoplasias/patologia
10.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067690

RESUMO

The melanin fluorescence emitted by pigment cells of the human skin has been a central research topic for decades, because melanin, on the one hand, protects against (solar) radiation in the near-UV range, whereas on the other hand, melanocytes are the starting point for the malignant transformation into melanoma. Until recently, however, melanin fluorescence was not accessible in the context of conventional spectroscopy, because it is ultraweak and is overshadowed by the more intense so-called autofluorescence of endogenous fluorophores. The advent of a new method of laser spectroscopy has made this melanin fluorescence measurable in vivo. A stepwise two-photon absorption with 800 nm photons is used, which more selectively excites melanin (dermatofluoroscopy). Our review summarizes the experimental results on melanin fluorescence of the four types of cutaneous pigment cells from healthy and malignant tissues. Outstanding is the finding that different types of melanocytes (i.e., melanocytes of common nevi, versus dysplastic nevi or versus melanoma cells) show characteristically different fluorescence spectra. The possibilities of using this melanin fluorescence for melanoma diagnosis are shown. Moreover, the uniform fluorescence spectra emitted by different melanoma subtypes are essential. Conclusions are drawn about the molecular processes in the melanosomes that determine fluorescence. Finally, experimental suggestions for further investigations are given.


Assuntos
Melaninas/metabolismo , Melanócitos/metabolismo , Melanoma/metabolismo , Transformação Celular Neoplásica/patologia , Fluorescência , Humanos , Melaninas/análise , Melanoma/classificação , Melanoma/fisiopatologia , Pele/patologia , Neoplasias Cutâneas/patologia , Análise Espectral/métodos
11.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188561, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33965511

RESUMO

Paired box 9 (PAX9) gene belongs to the PAX family, which encodes a family of metazoan transcription factors documented by a conserved DNA binding paired domain 128-amino-acids, critically essential for physiology and development. It is primarily expressed in embryonic tissues, such as the pharyngeal pouch endoderm, somites, neural crest-derived mesenchyme, and distal limb buds. PAX9 plays a vital role in craniofacial development by maintaining the odontogenic potential, mutations, and polymorphisms associated with the risk of tooth agenesis, hypodontia, and crown size in dentition. The loss-of-function of PAX9 in the murine model resulted in a short life span due to the arrest of cleft palate formation and skeletal abnormalities. According to recent studies, the PAX9 gene has a significant role in maintaining squamous cell differentiation, odontoblast differentiation of pluripotent stem cells, deregulation of which is associated with tumor initiation, and malignant transformation. Moreover, PAX9 contributes to promoter hypermethylation and alcohol- induced oro-esophageal squamous cell carcinoma mediated by downregulation of differentiation and apoptosis. Likewise, PAX9 activation is also reported to be associated with drug sensitivity. In summary, this current review aims to understand PAX9 function in the regulation of development, differentiation, and carcinogenesis, along with the underlying signaling pathways for possible cancer therapeutics.


Assuntos
Transformação Celular Neoplásica/metabolismo , Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fator de Transcrição PAX9/metabolismo , Animais , Antineoplásicos/uso terapêutico , Apoptose , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Resistencia a Medicamentos Antineoplásicos , Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Terapia Genética , Humanos , Mutação , Neoplasias/genética , Neoplasias/patologia , Neoplasias/terapia , Células-Tronco Neoplásicas/patologia , Organogênese , Fator de Transcrição PAX9/genética , Polimorfismo de Nucleotídeo Único , Transdução de Sinais
12.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188566, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33992724

RESUMO

Accumulated evidence from genetically modified cell and animal models indicates that centrosome amplification (CA) can initiate tumorigenesis with metastatic potential and enhance cell invasion. Multiple human diseases are associated with CA and carcinogenesis as well as metastasis, including infection with oncogenic viruses, type 2 diabetes, toxicosis by environmental pollution and inflammatory disease. In this review, we summarize (1) the evidence for the roles of CA in tumorigenesis and tumor cell invasion; (2) the association between diseases and carcinogenesis as well as metastasis; (3) the current knowledge of CA in the diseases; and (4) the signaling pathways of CA. We then give our own thinking and discuss perspectives relevant to CA in carcinogenesis and cancer metastasis in human diseases. In conclusion, investigations in this area might not only identify CA as a biological link between these diseases and the development of cancer but also prove the causal role of CA in cancer and progression under pathophysiological conditions, potentially taking cancer research into a new era.


Assuntos
Transformação Celular Neoplásica/patologia , Centrossomo/patologia , Neoplasias/patologia , Animais , Movimento Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Centrossomo/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias/genética , Neoplasias/metabolismo , Transdução de Sinais
13.
Methods Mol Biol ; 2262: 411-422, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33977492

RESUMO

Hyper-activation of RAS signaling pathways causes cancer, including melanoma, and RAS signaling pathways have been successfully targeted using drugs for patient benefit. The available drugs alone cannot cure cancer, however, and so investigation continues into RAS signaling pathways, with the goal of identifying further actionable targets. The zebrafish can be used to model human malignancies, and genetic modification of zebrafish to incorporate selective disease-associated genetic alterations is practicable. The following article describes the methods we are using to genetically modify zebrafish in order to dissect oncogenic RAS signaling in melanoma development.


Assuntos
Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Melanoma/patologia , Mutação , Transgenes/genética , Proteínas ras/metabolismo , Animais , Animais Geneticamente Modificados , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Humanos , Melanoma/genética , Melanoma/metabolismo , Peixe-Zebra , Proteínas ras/genética
14.
Toxins (Basel) ; 13(3)2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33804551

RESUMO

The tumor necrosis factor-α (TNF-α)-inducing protein (tipα) gene family, comprising Helicobacter pylori membrane protein 1 (hp-mp1) and tipα, has been identified as a tumor promoter, contributing to H. pylori carcinogenicity. Tipα is a unique H. pylori protein with no similarity to other pathogenicity factors, CagA, VacA, and urease. American H. pylori strains cause human gastric cancer, whereas African strains cause gastritis. The presence of Tipα in American and Euro-Asian strains suggests its involvement in human gastric cancer development. Tipα secreted from H. pylori stimulates gastric cancer development by inducing TNF-α, an endogenous tumor promoter, through its interaction with nucleolin, a Tipα receptor. This review covers the following topics: tumor-promoting activity of the Tipα family members HP-MP1 and Tipα, the mechanism underlying this activity of Tipα via binding to the cell-surface receptor, nucleolin, the crystal structure of rdel-Tipα and N-terminal truncated rTipα, inhibition of Tipα-associated gastric carcinogenesis by tumor suppressor B-cell translocation gene 2 (BTG2/TIS21), and new strategies to prevent and treat gastric cancer. Thus, Tipα contributes to the carcinogenicity of H. pylori by a mechanism that differs from those of CagA and VacA.


Assuntos
Antígenos de Bactérias/metabolismo , Proteínas da Membrana Bacteriana Externa/metabolismo , Proteínas de Bactérias/metabolismo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/metabolismo , Neoplasias Gástricas/microbiologia , Animais , Antígenos de Bactérias/genética , Proteínas da Membrana Bacteriana Externa/genética , Proteínas de Bactérias/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Transição Epitelial-Mesenquimal , Infecções por Helicobacter/complicações , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/terapia , Helicobacter pylori/genética , Helicobacter pylori/patogenicidade , Interações Hospedeiro-Patógeno , Humanos , Proteínas Imediatamente Precoces/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Fatores de Risco , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/prevenção & controle , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Supressoras de Tumor/metabolismo
16.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188534, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33794332

RESUMO

Mitochondria, well recognized as the "powerhouse" of cells, are maternally inherited organelles with bacterial ancestry that play essential roles in a myriad of cellular functions. It has become profoundly evident that mitochondria regulate a wide array of cellular and metabolic functions, including biosynthetic metabolism, cell signaling, redox homeostasis, and cell survival. Correspondingly, defects in normal mitochondrial functioning have been implicated in various human malignancies. Cancer development involves the activation of oncogenes, inactivation of tumor suppressor genes, and impairment of apoptotic programs in cells. Mitochondria have been recognized as the site of key metabolic switches for normal cells to acquire a malignant phenotype. This review outlines the role of mitochondria in human malignancies and highlights potential aspects of mitochondrial metabolism that could be targeted for therapeutic development.


Assuntos
Transformação Celular Neoplásica/metabolismo , Metabolismo Energético , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Oncogenes , Animais , Antineoplásicos/farmacologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Metabolismo Energético/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/patologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Transdução de Sinais
17.
Nat Commun ; 12(1): 2183, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846348

RESUMO

Here we show that FTO as an N6-methyladenosine (m6A) RNA demethylase is degraded by selective autophagy, which is impaired by low-level arsenic exposure to promote tumorigenesis. We found that in arsenic-associated human skin lesions, FTO is upregulated, while m6A RNA methylation is downregulated. In keratinocytes, chronic relevant low-level arsenic exposure upregulated FTO, downregulated m6A RNA methylation, and induced malignant transformation and tumorigenesis. FTO deletion inhibited arsenic-induced tumorigenesis. Moreover, in mice, epidermis-specific FTO deletion prevented skin tumorigenesis induced by arsenic and UVB irradiation. Targeting FTO genetically or pharmacologically inhibits the tumorigenicity of arsenic-transformed tumor cells. We identified NEDD4L as the m6A-modified gene target of FTO. Finally, arsenic stabilizes FTO protein through inhibiting p62-mediated selective autophagy. FTO upregulation can in turn inhibit autophagy, leading to a positive feedback loop to maintain FTO accumulation. Our study reveals FTO-mediated dysregulation of mRNA m6A methylation as an epitranscriptomic mechanism to promote arsenic tumorigenicity.


Assuntos
Adenosina/análogos & derivados , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Arsênio/toxicidade , Autofagia , Carcinogênese/genética , Adenosina/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Sequência de Bases , Carcinogênese/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/patologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Epiderme/metabolismo , Ontologia Genética , Células HEK293 , Células HaCaT , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Camundongos , NF-kappa B/metabolismo , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Estabilidade Proteica/efeitos dos fármacos , Estabilidade de RNA/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína Sequestossoma-1/metabolismo , Transcriptoma/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismo , Vacúolos/ultraestrutura
18.
Aging (Albany NY) ; 13(8): 11762-11773, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33878032

RESUMO

Aging plays an important role in many diseases, including breast cancer. Aged mammary stem/progenitor cells are perceived to be the cells of origin in breast tumorigenesis; however, the extensive use of mice who have aged naturally for research is hampered by cost, time, disease complications, and high mortality. In this study, we characterized murine mammary stem/progenitor cells in a D-galactose-induced accelerated aging model and compared them with findings from our earlier study on mice from natural aging. Our results showed that mammary glands in the D-galactose-induced aging model mimic natural aging in terms of pathological changes, epithelial cell composition, and mammary stem/progenitor cell function. These changes are accompanied by elevated inflammatory responses both systemically in the blood and locally in the mammary glands, which is similar in mice who age naturally. Our study for the first time evaluated the mammary glands and mammary stem/progenitor function in a D-galactose-induced aging model in rodents, and our findings suggest that D-galactose treatment can be used as a surrogate to study the role aged stem/progenitor cells play in breast tumorigenesis.


Assuntos
Envelhecimento/efeitos dos fármacos , Células Epiteliais/patologia , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/patologia , Células-Tronco/patologia , Envelhecimento/patologia , Animais , Diferenciação Celular/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/patologia , Células Epiteliais/efeitos dos fármacos , Feminino , Galactose/administração & dosagem , Galactose/toxicidade , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/efeitos dos fármacos , Neoplasias Mamárias Experimentais/induzido quimicamente , Camundongos , Células-Tronco/efeitos dos fármacos
19.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800170

RESUMO

IL-34 has been recently identified as a ligand for CSF1R that regulates various cellular processes including cell proliferation, survival, and differentiation. Although the binding of IL-34 to CSF1R modulates several cancer-driving signaling pathways, little is known about the role of IL-34/CSF1R signaling in breast cancer. Herein, we report that IL-34 induces epithelial cell transformation and breast tumorigenesis through activation of MEK/ERK and JNK/c-Jun pathways. IL-34 increased the phosphorylation of MEK1/2, ERK1/2, JNK1/2, and c-Jun through CSF1R in mouse skin epidermal JB6 C141 cells and human breast cancer MCF7 cells. IL-34 enhanced c-Fos and c-Jun promoter activity, resulting in increased AP-1 transactivation activity in JB6 Cl41 and MCF7 cells. Moreover, PIN1 enhanced IL-34-induced phosphorylation of MEK1/2, ERK1/2, JNK1/2, and c-Jun in JB6 Cl41 and MCF7 cells. Inhibition of PIN1 using juglone prevented the IL-34-induced transformation of JB6 C141 cells. Similarly, silencing of PIN1 reduced the IL-34-induced tumorigenicity of MCF7 cells. Consistent with these results, the synergistic model showed that treatment with juglone suppressed the IL-34-induced growth of tumors formed by 4T1 cells in BALB/c mice. Our study demonstrates the role of IL-34-induced MEK/ERK and JNK/c-Jun cascades in breast cancer and highlights the regulatory role of PIN1 in IL-34-induced breast tumorigenesis.


Assuntos
Neoplasias da Mama/metabolismo , Transformação Celular Neoplásica/metabolismo , Células Epiteliais/metabolismo , Interleucinas/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas de Neoplasias/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Animais , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/patologia , Células Epiteliais/patologia , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C
20.
Adv Anat Pathol ; 28(3): 107-118, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33825717

RESUMO

High-grade transformation (HGT) or dedifferentiation has been described in a variety of salivary gland carcinomas, including acinic cell carcinoma, secretory carcinoma, adenoid cystic carcinoma, epithelial-myoepithelial carcinoma, polymorphous adenocarcinoma, low-grade mucoepidermoid carcinoma, and hyalinizing clear cell carcinoma. High-grade (HG) transformed tumors are composed of a conventional low-grade component characterized by specific microscopic and immunohistochemical features for the given entity, intermingled with or juxtaposed to areas of HG morphology. This is usually either poorly differentiated adenocarcinoma, carcinoma not otherwise specified, or undifferentiated carcinoma, in which the original line of differentiation is lost. The HG component is composed of solid nests of anaplastic cells with large vesicular pleomorphic nuclei, prominent nucleoli, and abundant cytoplasm. Frequent mitoses and extensive necrosis may be present. The Ki-67 labeling index is consistently higher in the HG component. The molecular genetic mechanisms responsible for HGT of salivary gland carcinomas are largely unknown, though p53 inactivation and human epidermal growth factor receptor 2 overexpression and/or gene amplification have been demonstrated in the HG component in a few examples, the frequency varies for each histologic type. Salivary gland carcinomas with HGT are more aggressive than conventional carcinomas, with a higher local recurrence rate and a poorer prognosis. They have a high propensity for cervical lymph node metastasis suggesting a need for a wider resection and neck dissection. HGT of salivary gland carcinoma can occur either at initial presentation or less commonly at the time of recurrence, sometimes following postoperative radiotherapy. The potential for HGT in almost any type of salivary gland carcinoma warrants a thorough sampling of all salivary gland malignancies to prevent oversight of a HG component.


Assuntos
Carcinoma/patologia , Desdiferenciação Celular/fisiologia , Transformação Celular Neoplásica/patologia , Neoplasias das Glândulas Salivares/patologia , Glândulas Salivares/patologia , Biomarcadores Tumorais/genética , Carcinoma/genética , Transformação Celular Neoplásica/genética , Humanos , Receptor ErbB-2/genética , Neoplasias das Glândulas Salivares/genética
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