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1.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199046

RESUMO

Hyperglycemia may contribute to the progression of carcinomas by triggering epithelial-to-mesenchymal transition (EMT). Some proteostasis systems are involved in metastasis; in this paper, we sought to explore the mechanism of Hsp70 chaperone in EMT. We showed that knockdown of Hsp70 reduced cell migration capacity concomitantly with levels of mRNA of the Slug, Snail, and Twist markers of EMT, in colon cancer cells incubated in high glucose medium. Conversely, treatment of cells with Hsp70 inducer U-133 were found to elevate cell motility, along with the other EMT markers. To prove that inhibiting Hsp70 may reduce EMT efficiency, we treated cells with a CL-43 inhibitor of the HSF1 transcription factor, which lowered Hsp70 and HSF1 content in the control and induced EMT in carcinoma cells. Importantly, CL-43 reduced migration capacity, EMT-linked transcription factors, and increased content of epithelial marker E-cadherin in colon cancer cells of three lines, including one derived from a clinical sample. To prove that Hsp70 chaperone should be targeted when inhibiting the EMT pathway, we treated cancer cells with 2-phenylethynesulfonamide (PES) and demonstrated that the compound inhibited substrate-binding capacity of Hsp70. Furthermore, PES suppressed EMT features, cell motility, and expression of specific transcription factors. In conclusion, the Hsp70 chaperone machine efficiently protects mechanisms of the EMT, and the safe inhibitors of the chaperone are needed to hamper metastasis at its initial stage.


Assuntos
Glicemia , Transição Epitelial-Mesenquimal , Glucose/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Biomarcadores , Caderinas/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glucose/farmacologia , Humanos , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Ligação Proteica , Fatores de Transcrição da Família Snail/metabolismo
2.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209703

RESUMO

The M1/M2 macrophage paradigm plays a key role in tumor progression. M1 macrophages are historically regarded as anti-tumor, while M2-polarized macrophages, commonly deemed tumor-associated macrophages (TAMs), are contributors to many pro-tumorigenic outcomes in cancer through angiogenic and lymphangiogenic regulation, immune suppression, hypoxia induction, tumor cell proliferation, and metastasis. The tumor microenvironment (TME) can influence macrophage recruitment and polarization, giving way to these pro-tumorigenic outcomes. Investigating TME-induced macrophage polarization is critical for further understanding of TAM-related pro-tumor outcomes and potential development of new therapeutic approaches. This review explores the current understanding of TME-induced macrophage polarization and the role of M2-polarized macrophages in promoting tumor progression.


Assuntos
Ativação de Macrófagos/imunologia , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Animais , Biomarcadores , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Citocinas/metabolismo , Humanos , Hipóxia/genética , Hipóxia/imunologia , Hipóxia/metabolismo , Imunofenotipagem , Inflamação/etiologia , Inflamação/metabolismo , Ativação de Macrófagos/genética , Metástase Neoplásica , Estadiamento de Neoplasias , Transdução de Sinais , Macrófagos Associados a Tumor/patologia
3.
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
4.
Int J Mol Sci ; 22(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072237

RESUMO

In this review, we focus on bioinformatic oncology as an integrative discipline that incorporates knowledge from the mathematical, physical, and computational fields to further the biomedical understanding of cancer. Before providing a deeper insight into the bioinformatics approach and utilities involved in oncology, we must understand what is a system biology framework and the genetic connection, because of the high heterogenicity of the backgrounds of people approaching precision medicine. In fact, it is essential to providing general theoretical information on genomics, epigenomics, and transcriptomics to understand the phases of multi-omics approach. We consider how to create a multi-omics model. In the last section, we describe the new frontiers and future perspectives of this field.


Assuntos
Epigenômica , Genômica , Neoplasias/etiologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Aberrações Cromossômicas , Biologia Computacional/métodos , Suscetibilidade a Doenças , Epigenômica/métodos , Predisposição Genética para Doença , Genômica/métodos , Humanos , Aprendizado de Máquina , Medicina de Precisão , Proteômica/métodos , Transcriptoma
5.
Nat Commun ; 12(1): 3624, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131132

RESUMO

The LIM and SH3 domain protein 1 (Lasp1) was originally cloned from metastatic breast cancer and characterised as an adaptor molecule associated with tumourigenesis and cancer cell invasion. However, the regulation of Lasp1 and its function in the aggressive transformation of cells is unclear. Here we use integrative epigenomic profiling of invasive fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and from mouse models of the disease, to identify Lasp1 as an epigenomically co-modified region in chronic inflammatory arthritis and a functionally important binding partner of the Cadherin-11/ß-Catenin complex in zipper-like cell-to-cell contacts. In vitro, loss or blocking of Lasp1 alters pathological tissue formation, migratory behaviour and platelet-derived growth factor response of arthritic FLS. In arthritic human TNF transgenic mice, deletion of Lasp1 reduces arthritic joint destruction. Therefore, we show a function of Lasp1 in cellular junction formation and inflammatory tissue remodelling and identify Lasp1 as a potential target for treating inflammatory joint disorders associated with aggressive cellular transformation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Junções Aderentes/metabolismo , Artrite/metabolismo , Transformação Celular Neoplásica/metabolismo , Proteínas do Citoesqueleto/metabolismo , Fibroblastos/metabolismo , Proteínas com Domínio LIM/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Artrite/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Caderinas/metabolismo , Proteínas do Citoesqueleto/genética , Feminino , Proteínas de Homeodomínio , Proteínas com Domínio LIM/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos , beta Catenina/metabolismo
6.
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.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065204

RESUMO

Schwann cells are normally quiescent, myelinating glia cells of the peripheral nervous system. Their aberrant proliferation and transformation underlie the development of benign tumors (neurofibromas) as well as deadly malignant peripheral nerve sheath tumors (MPNSTs). We discovered a new driver of MPNSTs, an oncogenic GTPase named RABL6A, that functions in part by inhibiting the RB1 tumor suppressor. RB1 is a key mediator of cellular senescence, a permanent withdrawal from the cell cycle that protects against cell immortalization and transformation. Based on the RABL6A-RB1 link in MPNSTs, we explored the hypothesis that RABL6A promotes Schwann cell proliferation and abrogates their senescence by inhibiting RB1. Using sequentially passaged normal human Schwann cells (NHSCs), we found that the induction of replicative senescence was associated with reduced expression of endogenous RABL6A. Silencing RABL6A in low passage NHSCs caused premature stress-induced senescence, which was largely rescued by co-depletion of RB1. Consistent with those findings, Rabl6-deficient MEFs displayed impaired proliferation and accelerated senescence compared to wildtype MEFs. These results demonstrate that RABL6A is required for maintenance of proper Schwann cell proliferation and imply that aberrantly high RABL6A expression may facilitate malignant transformation.


Assuntos
Senescência Celular/fisiologia , Proteínas Oncogênicas/metabolismo , Proteínas de Ligação a Retinoblastoma/metabolismo , Células de Schwann/metabolismo , Células de Schwann/fisiologia , Ubiquitina-Proteína Ligases/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Carcinogênese/metabolismo , Ciclo Celular/fisiologia , Proliferação de Células/fisiologia , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Células HEK293 , Humanos , Neurofibroma/metabolismo , Neurofibrossarcoma/metabolismo
8.
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
9.
Nat Cell Biol ; 23(5): 497-510, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33972730

RESUMO

The Drosophila trachea, as the functional equivalent of mammalian blood vessels, senses hypoxia and oxygenates the body. Here, we show that the adult intestinal tracheae are dynamic and respond to enteric infection, oxidative agents and tumours with increased terminal branching. Increased tracheation is necessary for efficient damage-induced intestinal stem cell (ISC)-mediated regeneration and is sufficient to drive ISC proliferation in undamaged intestines. Gut damage or tumours induce HIF-1α (Sima in Drosophila), which stimulates tracheole branching via the FGF (Branchless (Bnl))-FGFR (Breathless (Btl)) signalling cascade. Bnl-Btl signalling is required in the intestinal epithelium and the trachea for efficient damage-induced tracheal remodelling and ISC proliferation. Chemical or Pseudomonas-generated reactive oxygen species directly affect the trachea and are necessary for branching and intestinal regeneration. Similarly, tracheole branching and the resulting increase in oxygenation are essential for intestinal tumour growth. We have identified a mechanism of tracheal-intestinal tissue communication, whereby damage and tumours induce neo-tracheogenesis in Drosophila, a process reminiscent of cancer-induced neoangiogenesis in mammals.


Assuntos
Transformação Celular Neoplásica/metabolismo , Hipóxia/metabolismo , Oxigênio/metabolismo , Regeneração/fisiologia , Animais , Animais Geneticamente Modificados/metabolismo , Proteínas de Ligação a DNA/metabolismo , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Receptores de Fatores de Crescimento de Fibroblastos/genética
10.
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
11.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33807071

RESUMO

Hepatocellular carcinoma (HCC), the most common malignant tumor in the liver, grows and metastasizes rapidly. Despite advances in treatment modalities, the five-year survival rate of HCC remains less than 30%. We sought genetic mutations that may affect the oncogenic properties of HCC, using The Cancer Genome Atlas (TCGA) data analysis. We found that the GNAQ T96S mutation (threonine 96 to serine alteration of the Gαq protein) was present in 12 out of 373 HCC patients (3.2%). To examine the effect of the GNAQ T96S mutation on HCC, we transfected the SK-Hep-1 cell line with the wild-type or the mutant GNAQ T96S expression vector. Transfection with the wild-type GNAQ expression vector enhanced anchorage-independent growth, migration, and the MAPK pathways in the SK-Hep-1 cells compared to control vector transfection. Moreover, cell proliferation, anchorage-independent growth, migration, and the MAPK pathways were further enhanced in the SK-Hep-1 cells transfected with the GNAQ T96S expression vector compared to the wild-type GNAQ-transfected cells. In silico structural analysis shows that the substitution of the GNAQ amino acid threonine 96 with a serine may destabilize the interaction between the regulator of G protein signaling (RGS) protein and GNAQ. This may reduce the inhibitory effect of RGS on GNAQ signaling, enhancing the GNAQ signaling pathway. Single nucleotide polymorphism (SNP) genotyping analysis for Korean HCC patients shows that the GNAQ T96S mutation was found in only one of the 456 patients (0.22%). Our data suggest that the GNAQ T96S hotspot mutation may play an oncogenic role in HCC by potentiating the GNAQ signal transduction pathway.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Mutação , Transdução de Sinais , Alelos , Substituição de Aminoácidos , Carcinoma Hepatocelular/patologia , Movimento Celular/genética , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Suscetibilidade a Doenças , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/química , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Expressão Gênica , Genótipo , Humanos , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases , Modelos Moleculares , Oncogenes , Conformação Proteica , Relação Estrutura-Atividade
12.
Int J Mol Sci ; 22(8)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33924087

RESUMO

Pepsin refluxate is considered a risk factor for laryngopharyngeal carcinogenesis. Non-acidic pepsin was previously linked to an inflammatory and tumorigenic effect on laryngopharyngeal cells in vitro. Yet there is no clear evidence of the pepsin-effect on a specific oncogenic pathway and the importance of pH in this process. We hypothesized that less acidic pepsin triggers the activation of a specific oncogenic factor and related-signalling pathway. To explore the pepsin-effect in vitro, we performed intermittent exposure of 15 min, once per day, for a 5-day period, of human hypopharyngeal primary cells (HCs) to pepsin (1 mg/mL), at a weakly acidic pH of 5.0, a slightly acidic pH of 6.0, and a neutral pH of 7.0. We have documented that the extracellular environment at pH 6.0, and particularly pH 7.0, vs. pH 5.0, promotes the pepsin-effect on HCs, causing increased internalized pepsin and cell viability, a pronounced activation of EGFR accompanied by NF-κB and STAT3 activation, and a significant upregulation of EGFR, AKT1, mTOR, IL1ß, TNF-α, RELA(p65), BCL-2, IL6 and STAT3. We herein provide new evidence of the pepsin-effect on oncogenic EGFR activation and its related-signaling pathway at neutral and slightly acidic pH in HCs, opening a window to further explore the prevention and therapeutic approach of laryngopharyngeal reflux disease.


Assuntos
Transformação Celular Neoplásica/metabolismo , Receptores ErbB/metabolismo , Concentração de Íons de Hidrogênio , Pepsina A/metabolismo , Transdução de Sinais , Sobrevivência Celular , Transformação Celular Neoplásica/genética , Células Cultivadas , Receptores ErbB/agonistas , Receptores ErbB/genética , Humanos , Hipofaringe/citologia , Hipofaringe/metabolismo , NF-kappa B/metabolismo , Pepsina A/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição STAT3/metabolismo
13.
Int J Mol Sci ; 22(6)2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33801148

RESUMO

Chemotherapeutics are the mainstay treatment for metastatic breast cancers. However, the chemotherapeutic failure caused by multidrug resistance (MDR) remains a pivotal obstacle to effective chemotherapies of breast cancer. Although in vitro evidence suggests that the overexpression of ATP-Binding Cassette (ABC) transporters confers resistance to cytotoxic and molecularly targeted chemotherapies by reducing the intracellular accumulation of active moieties, the clinical trials that target ABCB1 to reverse drug resistance have been disappointing. Nevertheless, studies indicate that ABC transporters may contribute to breast cancer development and metastasis independent of their efflux function. A broader and more clarified understanding of the functions and roles of ABC transporters in breast cancer biology will potentially contribute to stratifying patients for precision regimens and promote the development of novel therapies. Herein, we summarise the current knowledge relating to the mechanisms, functions and regulations of ABC transporters, with a focus on the roles of ABC transporters in breast cancer chemoresistance, progression and metastasis.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , Transportadores de Cassetes de Ligação de ATP/química , Transportadores de Cassetes de Ligação de ATP/classificação , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Progressão da Doença , Suscetibilidade a Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Família Multigênica , Metástase Neoplásica , Estadiamento de Neoplasias , Relação Estrutura-Atividade
14.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33806730

RESUMO

Depending on their tissue of origin, genetic and epigenetic marks and microenvironmental influences, cancer cells cover a broad range of metabolic activities that fluctuate over time and space. At the core of most metabolic pathways, mitochondria are essential organelles that participate in energy and biomass production, act as metabolic sensors, control cancer cell death, and initiate signaling pathways related to cancer cell migration, invasion, metastasis and resistance to treatments. While some mitochondrial modifications provide aggressive advantages to cancer cells, others are detrimental. This comprehensive review summarizes the current knowledge about mitochondrial transfers that can occur between cancer and nonmalignant cells. Among different mechanisms comprising gap junctions and cell-cell fusion, tunneling nanotubes are increasingly recognized as a main intercellular platform for unidirectional and bidirectional mitochondrial exchanges. Understanding their structure and functionality is an important task expected to generate new anticancer approaches aimed at interfering with gains of functions (e.g., cancer cell proliferation, migration, invasion, metastasis and chemoresistance) or damaged mitochondria elimination associated with mitochondrial transfer.


Assuntos
Mitocôndrias/genética , Mitocôndrias/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Animais , Transporte Biológico , Proliferação de Células , Sobrevivência Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Ciclo do Ácido Cítrico , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Metabolismo Energético , Humanos , Redes e Vias Metabólicas , Microtúbulos/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Fosforilação Oxidativa , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral
15.
BMC Cancer ; 21(1): 388, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33836673

RESUMO

BACKGROUND: Synonymous mutations do not change the protein sequences. Automatically, they have been regarded as neutral events and are ignored in the mutation-based cancer studies. However, synonymous mutations will change the codon optimality, resulting in altered translational velocity. METHODS: We fully utilized the transcriptome and translatome of liver cancer and normal tissue from ten patients. We profiled the mutation spectrum and examined the effect of synonymous mutations on translational velocity. RESULTS: Synonymous mutations that increase the codon optimality significantly enhanced the translational velocity, and were enriched in oncogenes. Meanwhile, synonymous mutations decreasing codon optimality slowed down translation, and were enriched in tumor suppressor genes. These synonymous mutations significantly contributed to the translational changes in tumor samples compared to normal samples. CONCLUSIONS: Synonymous mutations might play a role in liver cancer development by altering codon optimality and translational velocity. Synonymous mutations should no longer be ignored in the genome-wide studies.


Assuntos
Biomarcadores Tumorais , Transformação Celular Neoplásica/genética , Suscetibilidade a Doenças , Neoplasias Hepáticas/etiologia , Biossíntese de Proteínas , Mutação Silenciosa , Alelos , Transformação Celular Neoplásica/metabolismo , Mapeamento Cromossômico , Códon , Biologia Computacional/métodos , Bases de Dados Genéticas , Genes Supressores de Tumor , Humanos , Neoplasias Hepáticas/metabolismo , Oncogenes , Polimorfismo de Nucleotídeo Único
16.
BMC Cancer ; 21(1): 407, 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33853558

RESUMO

BACKGROUND: Pancreatic peritoneal carcinomatosis (PPC), with the worst median overall-survival (mOS), epitomizes the incurability of metastatic cancer. Cancer stem cells (CSCs) underpin this incurability. However, inhibitors of CSC-stemness fail to increase mOS in cancer patients despite preclinical tumor-reduction. This shortfall reinforces that preclinical efficacy should be defined by increased mOS in the presence of cancer comorbidities, CSC-heterogeneity and plasticity. The primary objectives of this study are: to test the dual endothelin-1/signal peptide receptor, DEspR, as a nodal therapeutic target in PPC, given DEspR induction in anoikis-resistant pancreatic CSCs, and to validate humanized anti-DEspR antibody, hu-6g8, as a potential therapeutic for PPC. METHODS: We used heterogeneous pools of CSCs selected for anoikis resistance from reprogrammed Panc1 and MiaPaCa2 tumor cells (TCs), and adherent TCs reprogrammed from CSCs (cscTCs). We used multiple anti-DEspR blocking antibodies (mAbs) with different epitopes, and a humanized anti-DEspR recombinant mAb cross-reactive in rodents and humans, to test DEspR inhibition effects. We measured DEspR-inhibition efficacy on multiple prometastatic CSC-functions in vitro, and on tumorigenesis and overall survival in a CSC-derived xenograft (CDX) nude rat model of PPC with comorbidities. RESULTS: Here we show that DEspR, a stress-survival receptor, is present on subsets of PDAC Panc1-TCs, TC-derived CSCs, and CSC-differentiated TCs (cscTCs), and that DESpR-inhibition decreases apoptosis-resistance and pro-metastatic mesenchymal functions of CSCs and cscTCs in vitro. We resolve the DNA-sequence/protein-function discordance by confirming ADAR1-RNA editing-dependent DEspR-protein expression in Panc1 and MiaPaCa2 TCs. To advance DEspR-inhibition as a nodal therapeutic approach for PPC, we developed and show improved functionality of a recombinant, humanized anti-DEspR IgG4S228P antibody, hu-6g8, over murine precursor anti-DEspR mabs. Hu-6g8 internalizes and translocates to the nucleus colocalized with cyto-nuclear shuttling galectins-1/3, and induces apoptotic cell changes. DEspR-inhibition blocks transperitoneal dissemination and progression to peritoneal carcinomatosis of heterogeneous DEspR±/CD133 ± Panc1-derived CSCs in xenografted nude rats, improving mOS without chemotherapy-like adverse effects. Lastly, we show DEspR expression in Stage II-IV primary and invasive TCs in the stroma in PDAC-patient tumor arrays. CONCLUSION: Collectively, the data support humanized anti-DEspR hu-6g8 as a potential targeted antibody-therapeutic with promising efficacy, safety and prevalence profiles for PPC patients.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/farmacologia , Imunoglobulina G/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/secundário , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Anticorpos Monoclonais Humanizados/química , Antineoplásicos Imunológicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Imunoglobulina G/química , Imuno-Histoquímica , Imunofenotipagem , Neoplasias Pancreáticas/patologia , Ratos , Receptor de Endotelina A , Ensaios Antitumorais Modelo de Xenoenxerto
17.
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
18.
Front Immunol ; 12: 612271, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33889150

RESUMO

Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide and is predicted to become second in 2030 in industrialized countries if no therapeutic progress is made. Among the different types of pancreatic cancers, Pancreatic Ductal Adenocarcinoma (PDAC) is by far the most represented one with an occurrence of more than 90%. This specific cancer is a devastating malignancy with an extremely poor prognosis, as shown by the 5-years survival rate of 2-9%, ranking firmly last amongst all cancer sites in terms of prognostic outcomes for patients. Pancreatic tumors progress with few specific symptoms and are thus at an advanced stage at diagnosis in most patients. This malignancy is characterized by an extremely dense stroma deposition around lesions, accompanied by tissue hypovascularization and a profound immune suppression. Altogether, these combined features make access to cancer cells almost impossible for conventional chemotherapeutics and new immunotherapeutic agents, thus contributing to the fatal outcomes of the disease. Initially ignored, the Tumor MicroEnvironment (TME) is now the subject of intensive research related to PDAC treatment and could contain new therapeutic targets. In this review, we will summarize the current state of knowledge in the field by focusing on TME composition to understand how this specific compartment could influence tumor progression and resistance to therapies. Attention will be paid to Tenascin-C, a matrix glycoprotein commonly upregulated during cancer that participates to PDAC progression and thus contributes to poor prognosis.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Proteínas da Matriz Extracelular/metabolismo , Neoplasias Pancreáticas/metabolismo , Células Estromais/metabolismo , Animais , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Carcinoma Ductal Pancreático/etiologia , Carcinoma Ductal Pancreático/terapia , Transformação Celular Neoplásica/metabolismo , Humanos , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Células Estromais/patologia , Microambiente Tumoral
19.
Int J Biol Macromol ; 182: 264-275, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33836193

RESUMO

Deleted in liver cancer 1 (DLC1) is a recognized tumor suppressor gene that negatively regulates Rho family proteins by hydrolyzing the active GTP-bound state to its inactive GDP-bound state. Active Rho proteins play a positive role in tumorigenesis. Numerous in vitro and in vivo experiments have shown that DLC1 is downregulated or inactivated in various solid tumors, which may be due to the following five reasons: genomic deletion, epigenetic modification and ubiquitin-dependent proteasomal degradation may cause DLC1 underexpression; phosphorylation at the post-translation level may cause DLC1 inactivation; and failure to localize at focal adhesions (FAs) may prevent DLC1 from exerting full activity. All of the causes could be attributed to molecular binding. Experimental evidence suggests that direct or indirect targeting of DLC1 is feasible for cancer treatment. Therefore, elucidating the interaction of DLC1 with its binding partners might provide novel targeted therapies for cancer. In this review, we summarized the binding partners of DLC1 at both the gene and protein levels and expounded a variety of anticancer drugs targeting DLC1 to provide information about DLC1 as a cancer diagnostic indicator or therapeutic target.


Assuntos
Proteínas Ativadoras de GTPase/metabolismo , Neoplasias/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Transformação Celular Neoplásica/metabolismo , Proteínas Ativadoras de GTPase/antagonistas & inibidores , Proteínas Ativadoras de GTPase/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética
20.
Nat Commun ; 12(1): 1502, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33686070

RESUMO

It is unclear how genetic aberrations impact the state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) has been shown to arise from luminal progenitors yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that perturbing Brca1/p53 in luminal progenitors induces aberrant alveolar differentiation pre-malignancy accompanied by pro-tumourigenic changes in the immune compartment. Unlike alveolar differentiation during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Based on our data we propose a model where Brca1/p53 LOF inadvertently promotes a differentiation program hardwired in luminal progenitors, highlighting the deterministic role of the cell-of-origin and offering a potential explanation for the tissue specificity of BRCA1 tumours.


Assuntos
Proteína BRCA1/genética , Transformação Celular Neoplásica/genética , Neoplasias Mamárias Experimentais/genética , Fenobarbital/metabolismo , Análise de Célula Única/métodos , Células-Tronco/patologia , Animais , Proteína BRCA1/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Comunicação Celular/fisiologia , Diferenciação Celular/fisiologia , Transformação Celular Neoplásica/metabolismo , Feminino , Humanos , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Mutação , Células-Tronco/fisiologia , Microambiente Tumoral/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
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