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1.
Adv Exp Med Biol ; 1280: 243-260, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33791987

RESUMEN

Oxygen is directly involved in many key pathophysiological processes. Oxygen deficiency, also known as hypoxia, could have adverse effects on mammalian cells, with ischemia in vital tissues being the most significant (Michiels C. Physiological and pathological responses to hypoxia. Am J Pathol 164(6): 1875-1882, 2004); therefore, timely adaptive responses to variations in oxygen availability are essential for cellular homeostasis and survival. The most critical molecular event in hypoxic response is the activation and stabilization of a transcriptional factor termed hypoxia-induced factor-1 (HIF-1) that is responsible for the upregulation of many downstream effector genes, collectively known as hypoxia-responsive genes. Multiple key biological pathways such as proliferation, energy metabolism, invasion, and metastasis are governed by these genes; thus, HIF-1-mediated pathways are equally pivotal in both physiology and pathology.As we gain knowledge on the molecular mechanisms underlying the regulation of HIF-1, a great focus has been placed on elucidating the cellular function of HIF-1, particularly the role of HIF-1 in cancer pathogenesis pathways such as proliferation, invasion, angiogenesis, and metastasis. In cancer, HIF-1 is directly involved in the shift of cancer tissues from oxidative phosphorylation to aerobic glycolysis, a phenomenon known as the Warburg effect. Although targeting HIF-1 as a cancer therapy seems like an extremely rational approach, owing to the complex network of its downstream effector genes, the development of specific HIF-1 inhibitors with fewer side effects and more specificity has not been achieved. Therefore, in this review, we provide a brief background about the function of HIF proteins in hypoxia response with a special emphasis on the unique role played by HIF-1α in cancer growth and invasiveness, in the hypoxia response context.


Asunto(s)
Neoplasias , Animales , Hipoxia de la Célula , Humanos , Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Redes y Vías Metabólicas , Neoplasias/genética , Neovascularización Patológica/genética
2.
Front Immunol ; 12: 597399, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33796097

RESUMEN

There exists increasing evidence that people with preceding medical conditions, such as diabetes and cancer, have a higher risk of infection with SARS-CoV-2 and are more vulnerable to severe disease. To get insights into the possible role of the immune system upon COVID-19 infection, 2811 genes of the gene ontology term "immune system process GO: 0002376" were selected for coexpression analysis of the human targets of SARS-CoV-2 (HT-SARS-CoV-2) ACE2, TMPRSS2, and FURIN in tissue samples from patients with cancer and diabetes mellitus. The network between HT-SARS-CoV-2 and immune system process genes was analyzed based on functional protein associations using STRING. In addition, STITCH was employed to determine druggable targets. DPP4 was the only immune system process gene, which was coexpressed with the three HT-SARS-CoV-2 genes, while eight other immune genes were at least coexpressed with two HT-SARS-CoV-2 genes. STRING analysis between immune and HT-SARS-CoV-2 genes plotted 19 associations of which there were eight common networking genes in mixed healthy (323) and pan-cancer (11003) tissues in addition to normal (87), cancer (90), and diabetic (128) pancreatic tissues. Using this approach, three commonly applicable druggable connections between HT-SARS-CoV-2 and immune system process genes were identified. These include positive associations of ACE2-DPP4 and TMPRSS2-SRC as well as a negative association of FURIN with ADAM17. Furthermore, 16 drugs were extracted from STITCH (score <0.8) with 32 target genes. Thus, an immunological network associated with HT-SARS-CoV-2 using bioinformatics tools was identified leading to novel therapeutic opportunities for COVID-19.


Asunto(s)
Diabetes Mellitus/metabolismo , Neoplasias/metabolismo , /metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , /genética , Antivirales/química , Antivirales/farmacología , /genética , /metabolismo , Bases de Datos Genéticas , Diabetes Mellitus/genética , Diabetes Mellitus/inmunología , Diabetes Mellitus/virología , Dipeptidil Peptidasa 4/genética , Dipeptidil Peptidasa 4/metabolismo , Furina/genética , Furina/metabolismo , Regulación de la Expresión Génica/inmunología , Ontología de Genes , Estudio de Asociación del Genoma Completo , Genómica , Humanos , Linfocitos/inmunología , Linfocitos/metabolismo , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/virología , Páncreas/inmunología , Páncreas/metabolismo , Páncreas/virología , Mapas de Interacción de Proteínas/genética , Mapas de Interacción de Proteínas/inmunología , /inmunología , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo
3.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809200

RESUMEN

During its evolution, cancer induces changes in patients' energy metabolism that strongly affect the overall clinical state and are responsible for cancer-related cachexia syndrome. To better understand the mechanisms underlying cachexia and its metabolic derangements, research efforts should focus on the events that are driven by the immune system activation during the evolution of neoplastic disease and on the phenomena of "resistance" and "tolerance" typically involved in the human body response against stress, pathogens, or cancer. Indeed, in the case where resistance is not able to eliminate the cancer, tolerance mechanisms can utilize the symptoms of cachexia (anemia, anorexia, and fatigue) to counteract unregulated cancer growth. These notions are also sustained by the evidence that cancer cachexia may be reversible if the resistance and tolerance phases are supported by appropriate antineoplastic treatments. Accordingly, there is no doubt that anticachectic therapies have an irreplaceable role in cases of reversible cancer cachexia where, if harmoniously associated with effective antineoplastic therapies, they can contribute to preserve the quality of life and improve prognosis. Such anticachectic treatments should be based on targeting the complex immunological, inflammatory, and metabolic pathways involved in the complex pathogenesis of cachexia. Meanwhile, the role of the anticachectic therapies is very different in the stage of irreversible cachexia when the available antineoplastic treatments are not able to control the disease and the resistance mechanisms fail with the prevalence of the tolerance phenomena. At this stage, they can be useful only to improve the quality of life, allowing the patient and their family to get a better awareness of the final phases of life, thereby opening to the best spiritual remodulation of the final event, death.


Asunto(s)
Caquexia/genética , Metabolismo Energético/genética , Tolerancia Inmunológica/genética , Neoplasias/genética , Anorexia/genética , Anorexia/metabolismo , Anorexia/patología , Caquexia/complicaciones , Caquexia/metabolismo , Caquexia/patología , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Neoplasias/complicaciones , Neoplasias/metabolismo , Neoplasias/patología , Pronóstico , Calidad de Vida
4.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809369

RESUMEN

T cells play a key role in tumour surveillance, both identifying and eliminating transformed cells. However, as tumours become established they form their own suppressive microenvironments capable of shutting down T cell function, and allowing tumours to persist and grow. To further understand the tumour microenvironment, including the interplay between different immune cells and their role in anti-tumour immune responses, a number of studies from mouse models to clinical trials have been performed. In this review, we examine mechanisms utilized by tumour cells to reduce their visibility to CD8+ Cytotoxic T lymphocytes (CTL), as well as therapeutic strategies trialled to overcome these tumour-evasion mechanisms. Next, we summarize recent advances in approaches to enhance CAR T cell activity and persistence over the past 10 years, including bispecific CAR T cell design and early evidence of efficacy. Lastly, we examine mechanisms of T cell infiltration and tumour regression, and discuss the strengths and weaknesses of different strategies to investigate T cell function in murine tumour models.


Asunto(s)
Inmunoterapia , Neoplasias/inmunología , Linfocitos T/inmunología , Microambiente Tumoral/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Humanos , Ratones , Neoplasias/genética , Neoplasias/terapia , Linfocitos T Citotóxicos/inmunología
5.
Adv Exp Med Biol ; 1308: 13-23, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33861433

RESUMEN

Phytochemicals are various compounds produced by plants. There is growing evidence on their potential health effects. Some of these compounds are considered as traditional medicines and used as painkillers, anti-inflammatory agents, and for other applications. One of these phytochemicals is curumin, a natural polyphenol derived from the turmeric plant (Curcuma longa L.). Curcumin is widely used as a food coloring, preservative and condiment. It has also been shown to have antioxidative and anti-inflammatory effects. Moreover, there is growing evidence that curcumin alters long noncoding RNAs (lncRNAs) in many kinds of cancer. These noncoding RNAs can cause epigenetic modulation in the expression of several genes. This study reviews reports of curcumin effects on lncRNAs in lung, prostate, colorectal, breast, pancreatic, renal, gastric, and ovarian cancers.


Asunto(s)
Curcumina , Neoplasias , ARN Largo no Codificante , Antiinflamatorios/uso terapéutico , Curcumina/farmacología , Curcumina/uso terapéutico , Humanos , Masculino , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Fitoquímicos/uso terapéutico , ARN Largo no Codificante/genética , ARN Largo no Codificante/uso terapéutico
6.
Nat Commun ; 12(1): 2031, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33795676

RESUMEN

Patient-derived xenografts are crucial for drug development but their use is challenged by issues such as murine viral infection. We evaluate the scope of viral infection and its impact on patient-derived xenografts by taking an unbiased data-driven approach to analyze unmapped RNA-Seq reads from 184 experiments. We find and experimentally validate the extensive presence of murine viral sequence reads covering entire viral genomes in patient-derived xenografts. The existence of viral sequences inside tumor cells is further confirmed by single cell sequencing data. Extensive chimeric reads containing both viral and human sequences are also observed. Furthermore, we find significantly changed expression levels of many cancer-, immune-, and drug metabolism-related genes in samples with high virus load. Our analyses indicate a need to carefully evaluate the impact of viral infection on patient-derived xenografts for drug development. They also point to a need for attention to quality control of patient-derived xenograft experiments.


Asunto(s)
Genoma Viral/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias/genética , Análisis de Secuencia de ADN/métodos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Línea Celular Tumoral , Productos del Gen env/clasificación , Productos del Gen env/genética , Productos del Gen gag/clasificación , Productos del Gen gag/genética , Xenoinjertos/metabolismo , Xenoinjertos/virología , Humanos , Ratones , Neoplasias/clasificación , Neoplasias/virología , Filogenia , Virosis/genética , Virosis/virología
7.
Nat Rev Cancer ; 21(5): 279, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33790461
8.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799762

RESUMEN

Pseudoxanthoma elasticum (PXE) is a complex autosomal recessive disease caused by mutations of ABCC6 transporter and characterized by ectopic mineralization of soft connective tissues. Compared to the other ABC transporters, very few studies are available to explain the structural components and working of a full ABCC6 transporter, which may provide some idea about its physiological role in humans. Some studies suggest that mutations of ABCC6 in the liver lead to a decrease in some circulating factor and indicate that PXE is a metabolic disease. It has been reported that ABCC6 mediates the efflux of ATP, which is hydrolyzed in PPi and AMP; in the extracellular milieu, PPi gives potent anti-mineralization effect, whereas AMP is hydrolyzed to Pi and adenosine which affects some cellular properties by modulating the purinergic pathway. Structural and functional studies have demonstrated that silencing or inhibition of ABCC6 with probenecid changed the expression of several genes and proteins such as NT5E and TNAP, as well as Lamin, and CDK1, which are involved in cell motility and cell cycle. Furthermore, a change in cytoskeleton rearrangement and decreased motility of HepG2 cells makes ABCC6 a potential target for anti-cancer therapy. Collectively, these findings suggested that ABCC6 transporter performs functions that modify both the external and internal compartments of the cells.


Asunto(s)
Hepatocitos/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Mutación , Neoplasias/genética , Seudoxantoma Elástico/genética , Animales , Antineoplásicos/uso terapéutico , Resistencia a Medicamentos/genética , Células Hep G2 , Humanos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Seudoxantoma Elástico/metabolismo
9.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799880

RESUMEN

Leptin is an obesity-associated adipokine that is known to regulate energy metabolism and reproduction and to control appetite via the leptin receptor. Recent work has identified specific cell types other than adipocytes that harbor leptin and leptin receptor expression, particularly in cancers and tumor microenvironments, and characterized the role of this signaling axis in cancer progression. Furthermore, the prognostic significance of leptin in various types of cancer and the ability to noninvasively detect leptin levels in serum samples have attracted attention for potential clinical applications. Emerging findings have demonstrated the direct and indirect biological effects of leptin in regulating cancer proliferation, metastasis, angiogenesis and chemoresistance, warranting the exploration of the underlying molecular mechanisms to develop a novel therapeutic strategy. In this review article, we summarize and integrate transcriptome and clinical data from cancer patients together with the recent findings related to the leptin signaling axis in the aforementioned malignant phenotypes. In addition, a comprehensive analysis of leptin and leptin receptor distribution in a pancancer panel and in individual cell types of specific organs at the single-cell level is presented, identifying those sites that are prone to leptin-mediated tumorigenesis. Our results shed light on the role of leptin in cancer and provide guidance and potential directions for further research for scientists in this field.


Asunto(s)
Carcinogénesis/metabolismo , Leptina/metabolismo , Neoplasias/metabolismo , Obesidad/metabolismo , Transducción de Señal , Adipocitos/metabolismo , Animales , Carcinogénesis/genética , Humanos , Neoplasias/genética , Neoplasias/patología , Obesidad/genética , Receptores de Leptina/genética , Receptores de Leptina/metabolismo , Microambiente Tumoral/genética
10.
Nat Commun ; 12(1): 2121, 2021 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-33837189

RESUMEN

Prime editors (PEs) mediate genome modification without utilizing double-stranded DNA breaks or exogenous donor DNA as a template. PEs facilitate nucleotide substitutions or local insertions or deletions within the genome based on the template sequence encoded within the prime editing guide RNA (pegRNA). However, the efficacy of prime editing in adult mice has not been established. Here we report an NLS-optimized SpCas9-based prime editor that improves genome editing efficiency in both fluorescent reporter cells and at endogenous loci in cultured cell lines. Using this genome modification system, we could also seed tumor formation through somatic cell editing in the adult mouse. Finally, we successfully utilize dual adeno-associated virus (AAVs) for the delivery of a split-intein prime editor and demonstrate that this system enables the correction of a pathogenic mutation in the mouse liver. Our findings further establish the broad potential of this genome editing technology for the directed installation of sequence modifications in vivo, with important implications for disease modeling and correction.


Asunto(s)
Carcinogénesis/genética , Edición Génica/métodos , Neoplasias/genética , ARN Guia/genética , Alelos , Animales , Sistemas CRISPR-Cas/genética , Dependovirus/genética , Modelos Animales de Enfermedad , Células HEK293 , Células HeLa , Humanos , Ratones , Neoplasias/patología , Transfección
11.
Nat Commun ; 12(1): 2345, 2021 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-33879792

RESUMEN

Age is the most important risk factor for cancer, as cancer incidence and mortality increase with age. However, how molecular alterations in tumours differ among patients of different age remains largely unexplored. Here, using data from The Cancer Genome Atlas, we comprehensively characterise genomic, transcriptomic and epigenetic alterations in relation to patients' age across cancer types. We show that tumours from older patients present an overall increase in genomic instability, somatic copy-number alterations (SCNAs) and somatic mutations. Age-associated SCNAs and mutations are identified in several cancer-driver genes across different cancer types. The largest age-related genomic differences are found in gliomas and endometrial cancer. We identify age-related global transcriptomic changes and demonstrate that these genes are in part regulated by age-associated DNA methylation changes. This study provides a comprehensive, multi-omics view of age-associated alterations in cancer and underscores age as an important factor to consider in cancer research and clinical practice.


Asunto(s)
Envejecimiento/genética , Neoplasias/etiología , Neoplasias/genética , Factores de Edad , Envejecimiento/metabolismo , Variaciones en el Número de Copia de ADN , Metilación de ADN , Bases de Datos Genéticas , Epigénesis Genética , Femenino , Duplicación de Gen , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Genoma Humano , Inestabilidad Genómica , Genómica , Humanos , Pérdida de Heterocigocidad , Masculino , Mutación , Neoplasias/metabolismo , Oncogenes , Factores de Riesgo , Transducción de Señal/genética , Secuenciación Completa del Genoma
12.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799504

RESUMEN

Garcinol extracted from Garcinia indica fruit peel and leaves is a polyisoprenylated benzophenone. In traditional medicine it was used for its antioxidant and anti-inflammatory properties. Several studies have shown anti-cancer properties of garcinol in cancer cell lines and experimental animal models. Garcinol action in cancer cells is based on its antioxidant and anti-inflammatory properties, but also on its potency to inhibit histone acetyltransferases (HATs). Recent studies indicate that garcinol may also deregulate expression of miRNAs involved in tumour development and progression. This paper focuses on the latest research concerning garcinol as a HAT inhibitor and miRNA deregulator in the development and progression of various cancers. Garcinol may be considered as a candidate for next generation epigenetic drugs, but further studies are needed to establish the precise toxicity, dosages, routes of administration, and safety for patients.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Epigénesis Genética/efectos de los fármacos , Histona Acetiltransferasas/genética , MicroARNs/genética , Neoplasias/tratamiento farmacológico , Terpenos/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Dominio Catalítico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Garcinia/química , Regulación Neoplásica de la Expresión Génica , Histona Acetiltransferasas/antagonistas & inhibidores , Histona Acetiltransferasas/metabolismo , Humanos , MicroARNs/antagonistas & inhibidores , MicroARNs/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Extractos Vegetales/química
13.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799536

RESUMEN

In the last decades, the therapeutic potential of hematopoietic stem cell transplantation (HSCT) has acquired a primary role in the management of a broad spectrum of diseases including cancer, hematologic conditions, immune system dysregulations, and inborn errors of metabolism. The different types of HSCT, autologous and allogeneic, include risks of severe complications including acute and chronic graft-versus-host disease (GvHD) complications, hepatic veno-occlusive disease, lung injury, and infections. Despite being a dangerous procedure, it improved patient survival. Hence, its use was extended to treat autoimmune diseases, metabolic disorders, malignant infantile disorders, and hereditary skeletal dysplasia. HSCT is performed to restore or treat various congenital conditions in which immunologic functions are compromised, for instance, by chemo- and radiotherapy, and involves the administration of hematopoietic stem cells (HSCs) in patients with depleted or dysfunctional bone marrow (BM). Since HSCs biology is tightly regulated by oxidative stress (OS), the control of reactive oxygen species (ROS) levels is important to maintain their self-renewal capacity. In quiescent HSCs, low ROS levels are essential for stemness maintenance; however, physiological ROS levels promote HSC proliferation and differentiation. High ROS levels are mainly involved in short-term repopulation, whereas low ROS levels are associated with long-term repopulating ability. In this review, we aim summarize the current state of knowledge about the role of ß3-adrenoreceptors (ß3-ARs) in regulating HSCs redox homeostasis. ß3-ARs play a major role in regulating stromal cell differentiation, and the antagonist SR59230A promotes differentiation of different progenitor cells in hematopoietic tumors, suggesting that ß3-ARs agonism and antagonism could be exploited for clinical benefit.


Asunto(s)
Enfermedades Hematológicas/genética , Células Madre Hematopoyéticas/metabolismo , Enfermedades del Sistema Inmune/genética , Neoplasias/genética , Especies Reactivas de Oxígeno/metabolismo , Receptores Adrenérgicos beta 3/genética , Antagonistas de Receptores Adrenérgicos beta 3/uso terapéutico , Animales , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Médula Ósea/patología , Regulación de la Expresión Génica , Enfermedades Hematológicas/tratamiento farmacológico , Enfermedades Hematológicas/inmunología , Enfermedades Hematológicas/patología , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/inmunología , Humanos , Enfermedades del Sistema Inmune/tratamiento farmacológico , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/patología , Errores Innatos del Metabolismo/tratamiento farmacológico , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/inmunología , Errores Innatos del Metabolismo/patología , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/patología , Estrés Oxidativo , Propanolaminas/uso terapéutico , Especies Reactivas de Oxígeno/inmunología , Receptores Adrenérgicos beta 3/inmunología , Trasplante Autólogo , Trasplante Homólogo
14.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799581

RESUMEN

A palindrome in DNA consists of two closely spaced or adjacent inverted repeats. Certain palindromes have important biological functions as parts of various cis-acting elements and protein binding sites. However, many palindromes are known as fragile sites in the genome, sites prone to chromosome breakage which can lead to various genetic rearrangements or even cell death. The ability of certain palindromes to initiate genetic recombination lies in their ability to form secondary structures in DNA which can cause replication stalling and double-strand breaks. Given their recombinogenic nature, it is not surprising that palindromes in the human genome are involved in genetic rearrangements in cancer cells as well as other known recurrent translocations and deletions associated with certain syndromes in humans. Here, we bring an overview of current understanding and knowledge on molecular mechanisms of palindrome recombinogenicity and discuss possible implications of DNA palindromes in carcinogenesis. Furthermore, we overview the data on known palindromic sequences in the human genome and efforts to estimate their number and distribution, as well as underlying mechanisms of genetic rearrangements specific palindromic sequences cause.


Asunto(s)
Carcinogénesis/genética , ADN de Neoplasias/genética , Secuencias Invertidas Repetidas , Neoplasias/genética , Recombinación Genética , Translocación Genética , Secuencia de Bases , Carcinogénesis/metabolismo , Carcinogénesis/patología , Biología Computacional/métodos , Replicación del ADN , ADN de Neoplasias/química , ADN de Neoplasias/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Genoma Humano , Inestabilidad Genómica , Humanos , Neoplasias/metabolismo , Neoplasias/patología , Conformación de Ácido Nucleico , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
15.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799592

RESUMEN

B-Cell Lymphoma 2 (BCL-2), c-MYC and related proteins are arguably amongst the most widely studied in all of biology. Every year there are thousands of papers reporting on different aspects of their biochemistry, cellular and physiological mechanisms and functions. This plethora of literature can be attributed to both proteins playing essential roles in the normal functioning of a cell, and by extension a whole organism, but also due to their central role in disease, most notably, cancer. Many cancers arise due to genetic lesions resulting in deregulation of both proteins, and indeed the development and survival of tumours is often dependent on co-operativity between these protein families. In this review we will discuss the individual roles of both proteins in cancer, describe cancers where co-operativity between them has been well-characterised and finally, some strategies to target these proteins therapeutically.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-myc/genética , Compuestos de Anilina/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Compuestos de Bifenilo/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Ensayos Clínicos como Asunto , Regulación Neoplásica de la Expresión Génica , Humanos , Morfolinos/uso terapéutico , Neoplasias/metabolismo , Neoplasias/patología , Nitrofenoles/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/uso terapéutico , Rituximab/uso terapéutico , Transducción de Señal , Sulfonamidas/uso terapéutico
16.
Medicine (Baltimore) ; 100(15): e25441, 2021 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-33847647

RESUMEN

INTRODUCTION: MiR-638 is believed to be involved in human cancers. However, the prognostic value of miR-638 in human carcinomas is controversial and inconclusive. Therefore, we conducted this meta-analysis to investigate the association between miR-638 expression and clinical outcomes in the patients with various cancers. METHODS: We searched Pubmed, Embase, Wanfang, and the China National Knowledge Infrastructure (CNKI) up to September 1, 2020 to identify relevant studies. Hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were used to correlate expression of miR-638 with prognosis and clinicopathological features. RESULTS: A total of 18 studies involving 1886 patients were included in the meta-analysis. The results revealed that low miR-638 expression was significantly correlated with poor overall survival (OS) (HR = 2.09, 95% CI: 1.46-2.98, P < .001), but not with disease-free survival (DFS) (HR = 1.71, 95% CI: 0.31-9.56, P = .540). Subgroup analysis found that low miR-638 expression was associated with worse OS in patients with digestive system cancer (HR = 2.47, 95% CI: 1.85-3.30, P < .001), the reported directly from articles group (HR = 2.12, 95% CI: 1.34-3.33, P < .001), survival curves group (HR = 2.02, 95% CI: 1.07-3.80, P = .029), in studies with sample size ≥100 (HR = 2.12, 95% CI: 1.34-3.35, P = .001), and in studies with sample size <100 (HR = 2.02, 95%CI: 1.09-3.75, P = .025). Moreover, cancer patients with low miR-638 expression were prone to tumor size (OR = 1.47, 95% CI: 1.03-2.09, P = .035), earlier lymph node metastasis (present vs absent, OR = 2.26, 95% CI: 1.63-3.14, P < .001), earlier distant metastasis (present vs absent, OR = 2.60, 95% CI: 1.45-4.67, P < .001), TNM stage (III-IV vs I-II, OR = 2.01, 95% CI: 1.35-2.99, P = .001), and portal vein invasion (present vs absent, OR = 4.39, 95% CI:2.23-8.64, P < .001), but not associated with age, gender, tumor differentiation, and vascular invasion. CONCLUSIONS: MiR-638 may serve as a promising indicator in the prediction of prognosis and clinicopathological features in patients with different kinds of cancers.


Asunto(s)
MicroARNs/análisis , Neoplasias/genética , Biomarcadores de Tumor/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Metástasis Linfática/genética , Masculino , Persona de Mediana Edad , Neoplasias/mortalidad , Oportunidad Relativa , Pronóstico , Modelos de Riesgos Proporcionales
17.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33802234

RESUMEN

Recent advances in sequencing and biotechnological methodologies have led to the generation of large volumes of molecular data of different omics layers, such as genomics, transcriptomics, proteomics and metabolomics. Integration of these data with clinical information provides new opportunities to discover how perturbations in biological processes lead to disease. Using data-driven approaches for the integration and interpretation of multi-omics data could stably identify links between structural and functional information and propose causal molecular networks with potential impact on cancer pathophysiology. This knowledge can then be used to improve disease diagnosis, prognosis, prevention, and therapy. This review will summarize and categorize the most current computational methodologies and tools for integration of distinct molecular layers in the context of translational cancer research and personalized therapy. Additionally, the bioinformatics tools Multi-Omics Factor Analysis (MOFA) and netDX will be tested using omics data from public cancer resources, to assess their overall robustness, provide reproducible workflows for gaining biological knowledge from multi-omics data, and to comprehensively understand the significantly perturbed biological entities in distinct cancer types. We show that the performed supervised and unsupervised analyses result in meaningful and novel findings.


Asunto(s)
Biomarcadores de Tumor , Biología Computacional , Genómica , Metabolómica , Neoplasias , Proteómica , Investigación en Medicina Traslacional , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/terapia
18.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807717

RESUMEN

Genes showing higher expression in either tumor or metastatic tissues can help in better understanding tumor formation and can serve as biomarkers of progression or as potential therapy targets. Our goal was to establish an integrated database using available transcriptome-level datasets and to create a web platform which enables the mining of this database by comparing normal, tumor and metastatic data across all genes in real time. We utilized data generated by either gene arrays from the Gene Expression Omnibus of the National Center for Biotechnology Information (NCBI-GEO) or RNA-seq from The Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and The Genotype-Tissue Expression (GTEx) repositories. The altered expression within different platforms was analyzed separately. Statistical significance was computed using Mann-Whitney or Kruskal-Wallis tests. False Discovery Rate (FDR) was computed using the Benjamini-Hochberg method. The entire database contains 56,938 samples, including 33,520 samples from 3180 gene chip-based studies (453 metastatic, 29,376 tumorous and 3691 normal samples), 11,010 samples from TCGA (394 metastatic, 9886 tumorous and 730 normal), 1193 samples from TARGET (1 metastatic, 1180 tumorous and 12 normal) and 11,215 normal samples from GTEx. The most consistently upregulated genes across multiple tumor types were TOP2A (FC = 7.8), SPP1 (FC = 7.0) and CENPA (FC = 6.03), and the most consistently downregulated gene was ADH1B (FC = 0.15). Validation of differential expression using equally sized training and test sets confirmed the reliability of the database in breast, colon, and lung cancer at an FDR below 10%. The online analysis platform enables unrestricted mining of the database and is accessible at TNMplot.com.


Asunto(s)
Bases de Datos de Ácidos Nucleicos , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Internet , Neoplasias , Programas Informáticos , Humanos , Metástasis de la Neoplasia , Neoplasias/genética , Neoplasias/metabolismo
19.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802672

RESUMEN

Raf kinase inhibitory protein (RKIP), also known as a phosphatidylethanolamine-binding protein 1 (PEBP1), functions as a tumor suppressor and regulates several signaling pathways, including ERK and NF-κκB. RKIP is severely downregulated in human malignant cancers, indicating a functional association with cancer metastasis and poor prognosis. The transcription regulation of RKIP gene in human cancers is not well understood. In this study, we suggested a possible transcription mechanism for the regulation of RKIP in human cancer cells. We found that Metadherin (MTDH) significantly repressed the transcriptional activity of RKIP gene. An analysis of publicly available datasets showed that the knockdown of MTDH in breast and endometrial cancer cell lines induced the expression RKIP. In addition, the results obtained from qRT-PCR and ChIP analyses showed that MTDH considerably inhibited RKIP expression. In addition, the RKIP transcript levels in MTDH-knockdown or MTDH-overexpressing MCF-7 cells were likely correlated to the protein levels, suggesting that MTDH regulates RKIP expression. In conclusion, we suggest that MTDH is a novel factor that controls the RKIP transcription, which is essential for cancer progression.


Asunto(s)
Progresión de la Enfermedad , Proteínas de la Membrana/metabolismo , Neoplasias/genética , Neoplasias/patología , Proteínas de Unión a Fosfatidiletanolamina/genética , Proteínas de Unión al ARN/metabolismo , Transcripción Genética , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Proteínas de la Membrana/genética , Mutación/genética , Regiones Promotoras Genéticas/genética , Unión Proteica , Proteínas de Unión al ARN/genética , Factores de Transcripción/metabolismo , Activación Transcripcional/genética , Regulación hacia Arriba/genética
20.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33804149

RESUMEN

In the last few decades, the newly emerging field of epigenetic regulation of glycosylation acquired more importance because it is unraveling physiological and pathological mechanisms related to glycan functions. Glycosylation is a complex process in which proteins and lipids are modified by the attachment of monosaccharides. The main actors in this kind of modification are the glycoenzymes, which are translated from glycosylation-related genes (or glycogenes). The expression of glycogenes is regulated by transcription factors and epigenetic mechanisms (mainly DNA methylation, histone acetylation and noncoding RNAs). This review focuses only on these last ones, in relation to cancer and other diseases, such as inflammatory bowel disease and IgA1 nephropathy. In fact, it is clear that a deeper knowledge in the fine-tuning of glycogenes is essential for acquiring new insights in the glycan field, especially if this could be useful for finding novel and personalized therapeutics.


Asunto(s)
Epigénesis Genética/genética , Neoplasias/genética , Procesamiento Proteico-Postraduccional/genética , ARN no Traducido/genética , Acetilación , Metilación de ADN/genética , Glicosilación , Humanos , Inmunoglobulina A/genética , Neoplasias/metabolismo , Polisacáridos/genética
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