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1.
Nat Cell Biol ; 22(4): 453-464, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32203417

RESUMEN

TAZ promotes growth, development and tumorigenesis by regulating the expression of target genes. However, the manner in which TAZ orchestrates the transcriptional responses is poorly defined. Here we demonstrate that TAZ forms nuclear condensates through liquid-liquid phase separation to compartmentalize its DNA-binding cofactor TEAD4, coactivators BRD4 and MED1, and the transcription elongation factor CDK9 for transcription. TAZ forms phase-separated droplets in vitro and liquid-like nuclear condensates in vivo, and this ability is negatively regulated by Hippo signalling through LATS-mediated phosphorylation and is mediated by the coiled-coil (CC) domain. Deletion of the TAZ CC domain or substitution with the YAP CC domain prevents the phase separation of TAZ and its ability to induce the expression of TAZ-specific target genes. Thus, we identify a mechanism of transcriptional activation by TAZ and demonstrate that pathway-specific transcription factors also engage the phase-separation mechanism for efficient and specific transcriptional activation.


Asunto(s)
Proteínas de Ciclo Celular/genética , Quinasa 9 Dependiente de la Ciclina/genética , Proteínas de Unión al ADN/genética , Subunidad 1 del Complejo Mediador/genética , Proteínas Musculares/genética , Transactivadores/genética , Factores de Transcripción/genética , Activación Transcripcional , Compartimento Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Quinasa 9 Dependiente de la Ciclina/metabolismo , Proteínas de Unión al ADN/metabolismo , Células HEK293 , Células HeLa , Humanos , Subunidad 1 del Complejo Mediador/metabolismo , Proteínas Musculares/metabolismo , Fosforilación , Dominios Proteicos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Transactivadores/metabolismo , Factores de Transcripción/metabolismo
2.
Chem Biol Interact ; 321: 109025, 2020 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-32135139

RESUMEN

Epigenetic regulation is one of the driving forces in the process of carcinogenesis. Corosolic acid (CA); triterpenoid abundantly found in Lagerstroemia speciosa L. is known to modulate various cellular process including cellular oxidative stress and signaling kinases in various diseases, including skin cancer. Genetic mutations in early stages of skin cancer are well-documented, the epigenetic alterations remain elusive. In the present study, we identified the transcriptomic gene expression changes with RNAseq and genome-wide DNA CpG methylation changes with DNA methylseq to profile the early stage transcriptomic and epigenomic changes using tumor promoter TPA-mediated mouse epidermal epithelial JB6 P+ cells. JB6 P+ cells were treated with TPA and Corosolic acid by 7.5uM optimized by MTS assay. Differentiated expressed genes (DEGs) and Differentially methylated genes (DMRs) were analyzed by R software. Ingenuity Pathway Analysis (IPA) was employed to understand the differential regulation of specific pathways. Novel TPA induced differentially overexpressed genes like tumor promoter Prl2c2, small prolin rich protein (Sprr2h) was reported which was downregulated by corosolic acid treatment. Several cancer related pathways were identified by Ingenuity Pathways Analysis (IPA) including p53, Erk, TGF beta signaling pathways. Moreover, differentially methylated regions (DMRs) in genes like Dusp22 (Dual specificity protein phosphatase 22), Rassf (tumor suppressor gene family, Ras association domain family) in JB6 P+ cells were uncovered which are altered by TPA and are reversed by CA treatment. Interestingly, genes like CDK1 (Cyclin-dependent kinases 1) and RASSF2 (Ras association domain family member 2) observed to be differentially methylated and expressed which was further modulated by corosolic acid treatment, validated by qPCR. Given study indicated gene expression changes to DNA CpG methylation epigenomic changes modulated various molecular pathways in TPA-induced JB6 cells and revealed that CA can potentially reverse these changes which deciphering novel molecular targets for future prevention of early stages of skin cancer studies in human.


Asunto(s)
Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Metilación de ADN/efectos de los fármacos , Células Epidérmicas/efectos de los fármacos , Células Epidérmicas/metabolismo , Triterpenos/farmacología , Animales , Carcinógenos/toxicidad , Línea Celular , Supervivencia Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Islas de CpG/efectos de los fármacos , Células Epidérmicas/patología , Epigénesis Genética/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ratones , Fitoquímicos/farmacología , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/metabolismo , Acetato de Tetradecanoilforbol/toxicidad , Transcriptoma/efectos de los fármacos
3.
Nat Commun ; 11(1): 1009, 2020 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-32081882

RESUMEN

The MEN1 gene, a tumor suppressor gene that encodes the protein menin, is mutated at high frequencies in neuroendocrine (NE) tumors; however, the biological importance of this gene in NE-type lung cancer in vivo remains unclear. Here, we established an ATII-specific KrasG12D/+/Men1-/- driven genetically engineered mouse model and show that deficiency of menin results in the accumulation of DNA damage and antagonizes oncogenic Kras-induced senescence and the epithelial-to-mesenchymal transition during lung tumorigenesis. The loss of menin expression in certain human primary lung cancers correlates with elevated NE profiles and reduced overall survival.


Asunto(s)
Daño del ADN/genética , Neoplasias Pulmonares/genética , Tumores Neuroendocrinos/genética , Proteínas Proto-Oncogénicas/deficiencia , Proteínas Proto-Oncogénicas/genética , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Diferenciación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Transición Epitelial-Mesenquimal/genética , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Noqueados , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)/genética , Transducción de Señal
4.
Anticancer Res ; 40(1): 169-176, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892565

RESUMEN

BACKGROUND/AIM: Cancer stem cells (CSCs) are considered to be one of the causes of tumor recurrence after chemotherapy. The purpose of our study was to isolate CSCs from human colorectal cancer cell (CRC) lines. MATERIALS AND METHODS: Nine CRC lines were screened based on the expression level of potential CSC markers to identify putative CSCs. Tumor formation capacity in immunodeficient mice was compared with that of their counterparts. Stemness, differentiation potency and sensitivity to 5-fluorouracil (5-FU), in vitro, were also assessed. Microarray analysis was used to characterize the features of the putative CSCs. RESULTS: COLO 201 cells were separated into two populations based on CD44 expression. CD44 positive (CD44+) cells showed significantly higher tumor formation capacity than CD44- cells in immunodeficient mice. CD44+ cells also possessed stemness properties and lower sensitivity to 5-FU in vitro. Moreover, cancer stemness and chemoresistance-related genes were highly up-regulated in CD44+ cells. CONCLUSION: CD44+ COLO 201 cells possessed the features of CSCs; therefore, the present CSC model could serve as a valuable tool to accelerate CSC research.


Asunto(s)
Receptores de Hialuranos/metabolismo , Células Madre Neoplásicas/metabolismo , Animales , Biomarcadores , Biomarcadores de Tumor , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Modelos Animales de Enfermedad , Citometría de Flujo , Fluorouracilo/farmacología , Xenoinjertos , Humanos , Receptores de Hialuranos/genética , Ratones
5.
Nat Rev Cancer ; 20(3): 158-173, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31907378

RESUMEN

For two decades, leukaemia stem cells (LSCs) in chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) have been advanced paradigms for the cancer stem cell field. In CML, the acquisition of the fusion tyrosine kinase BCR-ABL1 in a haematopoietic stem cell drives its transformation to become a LSC. In AML, LSCs can arise from multiple cell types through the activity of a number of oncogenic drivers and pre-leukaemic events, adding further layers of context and genetic and cellular heterogeneity to AML LSCs not observed in most cases of CML. Furthermore, LSCs from both AML and CML can be refractory to standard-of-care therapies and persist in patients, diversify clonally and serve as reservoirs to drive relapse, recurrence or progression to more aggressive forms. Despite these complexities, LSCs in both diseases share biological features, making them distinct from other CML or AML progenitor cells and from normal haematopoietic stem cells. These features may represent Achilles' heels against which novel therapies can be developed. Here, we review many of the similarities and differences that exist between LSCs in CML and AML and examine the therapeutic strategies that could be used to eradicate them.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/etiología , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/metabolismo , Células Madre Neoplásicas/metabolismo , Animales , Biomarcadores de Tumor , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/metabolismo , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Desarrollo de Medicamentos , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Terapia Molecular Dirigida , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Investigación/historia , Investigación/tendencias
6.
Cancer Immunol Immunother ; 69(2): 285-292, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31897662

RESUMEN

The wide-ranging collection of malignancies arising at the upper aerodigestive tract is categorized as head and neck cancer (HNC), the sixth most prevalent cancer worldwide. Infection with human papillomavirus (HPV) or exposure to carcinogens is the leading causes of HPV+ and HPV- HNCs development, respectively. HPV+ and HPV- HNCs are different in clinical and molecular aspects. Specifically, HPV- HNCs tightly associate with missense mutants of the TP53 gene (encoding for the p53 protein), suggesting a central role for mutant p53 gain-of-function (GOF) in driving tumorigenesis. In contrast, in HPV + HNC, the sequence of TP53 typically remains intact, while the protein is degraded. In tumor cells, the status of the TP53 gene affects the cargo of secreted exosomes. In this review, we describe the accumulated knowledge regarding the involvement of exosomes and p53 on cellular interactions between HPV+ and HPV- HNC cells, and the surrounding tumor microenvironment (TME). Moreover, we envision how TP53 status may determine exosomes cargo in HNC, and, consequently, modify the TME. The potential roles of exosomes described herein are based on both our studies and the studies of others on mutant p53-derived exosomes. Specifically, we showed how exosomes are shed by cancer cells harboring mutant p53 communicate with tumor-associated macrophages in the colon as well as with cancer-associated fibroblasts in the lung, creating immunosuppressive conditions and promoting invasiveness. Altogether, exosomes in HNC in the context of TP53 status are understudied and extensive research is required to shed light on the biology of HPV+ and HPV- HNC.


Asunto(s)
Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Exosomas/metabolismo , Neoplasias de Cabeza y Cuello/etiología , Neoplasias de Cabeza y Cuello/metabolismo , Mutación , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Animales , Susceptibilidad a Enfermedades , Matriz Extracelular/metabolismo , Predisposición Genética a la Enfermedad , Neoplasias de Cabeza y Cuello/patología , Humanos
7.
Int J Cancer ; 146(7): 1780-1790, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-31291465

RESUMEN

The prevalence of colorectal cancer (CRC) has markedly increased worldwide in the last decade. Alterations of bile acid metabolism and gut microbiota have been reported to play vital roles in intestinal carcinogenesis. About trillions of bacteria have inhabited in the human gut and maintained the balance of host metabolism. Bile acids are one of numerous metabolites that are synthesized in the liver and further metabolized by the gut microbiota, and are essential in maintaining the normal gut microbiota and lipid digestion. Multiple receptors such as FXR, GPBAR1, PXR, CAR and VDR act as sensors of bile acids have been reported. In this review, we mainly discussed interplay between bile acid metabolism and gut microbiota in intestinal carcinogenesis. We then summarized the critical role of bile acids receptors involving in CRC, and also addressed the rationale of multiple interventions for CRC management by regulating bile acids-microbiota axis such as probiotics, metformin, ursodeoxycholic acid and fecal microbiota transplantation. Thus, by targeting the bile acids-microbiota axis may provide novel therapeutic modalities in CRC prevention and treatment.


Asunto(s)
Transformación Celular Neoplásica/metabolismo , Microbioma Gastrointestinal , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Animales , Ácidos y Sales Biliares/metabolismo , Terapia Biológica , Biomarcadores , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Disbiosis , Microbioma Gastrointestinal/efectos de los fármacos , Humanos , Mucosa Intestinal/patología , Redes y Vías Metabólicas/efectos de los fármacos , Terapia Molecular Dirigida , Unión Proteica , Receptores Citoplasmáticos y Nucleares/metabolismo
8.
Cancer Sci ; 111(2): 418-428, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31799727

RESUMEN

MicroRNAs (miRNAs) fine-tune cellular signaling by regulating expression of signaling proteins, and aberrant expression of miRNAs is observed in many cancers. The tyrosine kinase c-Src is upregulated in various human cancers, but the molecular mechanisms underlying c-Src-mediated tumor progression remain unclear. In previous investigations of miRNA-mediated control of c-Src-related oncogenic pathways, we identified miRNAs that were downregulated in association with c-Src transformation and uncovered the signaling networks by predicting their target genes, which might act cooperatively to control tumor progression. Here, to further elucidate the process of cell transformation driven by c-Src, we analyzed the expression profiles of miRNAs in a doxycycline-inducible Src expression system. We found that miRNA (miR)-129-1-3p was downregulated in the early phase of c-Src-induced cell transformation, and that reexpression of miR-129-1-3p disrupted c-Src-induced cell transformation. In addition, miR-129-1-3p downregulation was tightly associated with tumor progression in human colon cancer cells/tissues. Expression of miR-129-1-3p in human colon cancer cells caused morphological changes and suppressed tumor growth, cell adhesion, and invasion. We also identified c-Src and its critical substrate Fer, and c-Yes, a member of the Src family of kinases, as novel targets of miR-129-1-3p. Furthermore, we found that miR-129-1-3p-mediated regulation of c-Src/Fer and c-Yes is important for controlling cell adhesion and invasion. Downregulation of miR-129-1-3p by early activation of c-Src increases expression of these target genes and synergistically promotes c-Src-related oncogenic signaling. Thus, c-Src-miR-129-1-3p circuits serve as critical triggers for tumor progression in many human cancers that harbor upregulation of c-Src.


Asunto(s)
/metabolismo , Transformación Celular Neoplásica/metabolismo , Neoplasias del Colon/metabolismo , Regulación hacia Abajo , MicroARNs/genética , Proteínas Proto-Oncogénicas pp60(c-src)/metabolismo , Animales , Movimiento Celular , Proliferación Celular , Transformación Celular Neoplásica/genética , Neoplasias del Colon/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Células HT29 , Humanos , Ratones , Trasplante de Neoplasias
9.
Biochim Biophys Acta Mol Cell Res ; 1867(1): 118573, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31678591

RESUMEN

Cytochrome c (Cyt c) released from mitochondria interacts with Apaf-1 to form the heptameric apoptosome, which initiates the caspase cascade to execute apoptosis. Although lysine residue at 72 (K72) of Cyt c plays an important role in the Cyt c-Apaf-1 interaction, the underlying mechanism of interaction between Cyt c and Apaf-1 is still not clearly defined. Here we identified multiple lysine residues including K72, which are also known to interact with ATP, to play a key role in Cyt c-Apaf-1 interaction. Mutation of these lysine residues abrogates the apoptosome formation causing inhibition of caspase activation. Using in-silico molecular docking, we have identified Cyt c-binding interface on Apaf-1. Although mutant Cyt c shows higher affinity for Apaf-1, the presence of Cyt c-WT restores the apoptosome activity. ATP addition modulates only mutant Cyt c binding to Apaf-1 but not WT Cyt c binding to Apaf-1. Using TCGA and cBioPortal, we identified multiple mutations in both Apaf-1 and Cyt c that are predicted to interfere with apoptosome assembly. We also demonstrate that transcript levels of various enzymes involved with dATP or ATP synthesis are increased in various cancers. Silencing of nucleotide metabolizing enzymes such as ribonucleotide reductase subunit M1 (RRM1) and ATP-producing glycolytic enzymes PKM2 attenuated ATP production and enhanced caspase activation. These findings suggest important role for lysine residues of Cyt c and nucleotides in the regulation of apoptosome-dependent apoptotic cell death as well as demonstrate how these mutations and nucleotides may have a pivotal role in human diseases such as cancer.


Asunto(s)
Apoptosomas/fisiología , Citocromos c/química , Simulación del Acoplamiento Molecular , Neoplasias/patología , Nucleótidos/química , Alanina/química , Alanina/genética , Sustitución de Aminoácidos , Apoptosomas/química , Factor Apoptótico 1 Activador de Proteasas/química , Factor Apoptótico 1 Activador de Proteasas/metabolismo , Estudios de Casos y Controles , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Células Cultivadas , Citocromos c/genética , Citocromos c/metabolismo , Femenino , Humanos , Lisina/química , Lisina/genética , Masculino , Modelos Moleculares , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Proteínas Mutantes/fisiología , Neoplasias/genética , Neoplasias/metabolismo , Nucleótidos/metabolismo , Células PC-3 , Unión Proteica/genética , Mapeo de Interacción de Proteínas , Multimerización de Proteína/genética , Transducción de Señal/genética
10.
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi ; 37(11): 806-809, 2019 Nov 20.
Artículo en Chino | MEDLINE | ID: mdl-31826542

RESUMEN

Objective: To investigate the expression and role of LINC00052 during glycidyl methacrylate (GMA) -induced malignant transformation of 16HBE cells. Methods: Human bronchial epithelial (16HBE) cells were divided into GMA transformation group and corresponding DMSO control group, and the 10th, 20th and 30th generation cells of each group were collected LncRNA microarrays were used to analysis expression of LINC00052 in different stage of malignant transformation. Bioinformatics analysis was applied and the relative expression of LINC00052 and its potentially target genes was detected by real-time quantification PCR (qPCR) . Results: The results of microarray analysis showed that LINC00052 was up-regulated by 1.32-fold, down-regulated by 1.64-fold and down-regulated by 4.92-fold in the malignant transformation early (P10) , middle term (P20) and late (P30) , respectively, The results of qPCR showed that compared with the DMSO control group, the expression of LINC00052 was up-regulated by 1.55 times, down-regulated by 1.20 times and down-regulated by 2.35 times in P10, P20 and P30, respectively, and the difference was statistically significant (P<0.05) . There was a statistically significant difference in the relative expression of NTRK3 between the GMA transformation group of P10 and P30 generations with the corresponding DMSO control group (P<0.05) . Conclusion: LINC00052 is highly expressed in early time of GMA-induced malignant transformation of 16HBE, and down-regulated in the middle and last stage of malignant transformation and may play a protective role in GMA-induced malignant transformation of 16HBE by influencing the expression of its target gene NTRK3.


Asunto(s)
Transformación Celular Neoplásica , Células Epiteliales , Compuestos Epoxi , Regulación Neoplásica de la Expresión Génica , Metacrilatos , ARN Largo no Codificante , Bronquios/citología , Línea Celular , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , ARN Largo no Codificante/genética
11.
Int J Mol Sci ; 20(19)2019 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-31623305

RESUMEN

Worldwide, several million workers are employed in the various chromium (Cr) industries. These workers may suffer from a variety of adverse health effects produced by dusts, mists and fumes containing Cr in the hexavalent oxidation state, Cr(VI). Of major importance, occupational exposure to Cr(VI) compounds has been firmly associated with the development of lung cancer. Counterintuitively, Cr(VI) is mostly unreactive towards most biomolecules, including nucleic acids. However, its intracellular reduction produces several species that react extensively with biomolecules. The diversity and chemical versatility of these species add great complexity to the study of the molecular mechanisms underlying Cr(VI) toxicity and carcinogenicity. As a consequence, these mechanisms are still poorly understood, in spite of intensive research efforts. Here, we discuss the impact of Cr(VI) on the stress response-an intricate cellular system against proteotoxic stress which is increasingly viewed as playing a critical role in carcinogenesis. This discussion is preceded by information regarding applications, chemical properties and adverse health effects of Cr(VI). A summary of our current understanding of cancer initiation, promotion and progression is also provided, followed by a brief description of the stress response and its links to cancer and by an overview of potential molecular mechanisms of Cr(VI) carcinogenicity.


Asunto(s)
Carcinógenos Ambientales/farmacología , Cromo/farmacología , Estrés Fisiológico/efectos de los fármacos , Carcinógenos Ambientales/toxicidad , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Cromo/toxicidad , Daño del ADN , Humanos , Neoplasias/etiología , Neoplasias/metabolismo , Neoplasias/patología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética
12.
Int J Mol Sci ; 20(19)2019 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-31623387

RESUMEN

Colorectal cancer (CRC) is one of the most common cancers in men and women worldwide as well as is the leading cause of death in the western world. Almost a third of the patients has or will develop liver metastases. While genetic as well as epigenetic mechanisms are important in CRC pathogenesis, the basis of the most cases of cancer is unknown. High spatial and inter-patient variability of the molecular alterations qualifies this cancer in the group of highly heterogeneous tumors, which makes it harder to elucidate the mechanisms underlying CRC progression. Determination of highly sensitive and specific early diagnosis markers and understanding the cellular and molecular mechanism(s) of cancer progression are still a challenge of the current era in oncology of solid tumors. One of the accepted risk factors for CRC development is overexpression of insulin-like growth factor 2 (IGF2), a 7.5-kDa peptide produced by liver and many other tissues. IGF2 is the first gene discovered to be parentally imprinted. Loss of imprinting (LOI) or aberrant imprinting of IGF2 could lead to IGF2 overexpression, increased cell proliferation, and CRC development. IGF2 as a mitogen is associated with increased risk of developing colorectal neoplasia. Higher serum IGF2 concentration as well as its tissue overexpression in CRC compared to control are associated with metastasis. IGF2 protein was one of the three candidates for a selective marker of CRC progression and staging. Recent research indicates dysregulation of different micro- and long non-coding RNAs (miRNAs and lncRNAs, respectively) embedded within the IGF2 gene in CRC carcinogenesis, with some of them indicated as potential diagnostic and prognostic CRC biomarkers. This review systematises the knowledge on the role of genetic and epigenetic instabilities of IGF2 gene, free (active form of IGF2) and IGF-binding protein (IGFBP) bound (inactive form), paracrine/autocrine secretion of IGF2, as well as mechanisms of inducing dysplasia in vitro and tumorigenicity in vivo. We have tried to answer which molecular changes of the IGF2 gene and its regulatory mechanisms have the most significance in initiation, progression (including liver metastasis), prognosis, and potential anti-IGF2 therapy in CRC patients.


Asunto(s)
Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/metabolismo , Factor II del Crecimiento Similar a la Insulina/metabolismo , Transducción de Señal , Animales , Biomarcadores de Tumor , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Susceptibilidad a Enfermedades , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Humanos , Factor II del Crecimiento Similar a la Insulina/genética , Terapia Molecular Dirigida , Estadificación de Neoplasias , Investigación en Medicina Traslacional
13.
Int J Mol Sci ; 20(20)2019 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-31600881

RESUMEN

Despite the different strategies used to treat ovarian cancer, around 70% of women/patients eventually fail to respond to the therapy. Cancer stem cells (CSCs) play a role in the treatment failure due to their chemoresistant properties. This capacity to resist chemotherapy allows CSCs to interact with different components of the tumor microenvironment, such as mesenchymal stem cells (MSCs), and thus contribute to tumorigenic processes. Although the participation of MSCs in tumor progression is well understood, it remains unclear how CSCs induce the pro-tumorigenic activity of MSCs in response to chemotherapy. Small extracellular vesicles, including exosomes, represent one possible way to modulate any type of cell. Therefore, in this study, we evaluate if small extracellular vesicle (sEV) derived from ovarian cancer spheroids (OCS), which are enriched in CSCs, can modify the activity of MSCs to a pro-tumorigenic phenotype. We show that sEV released by OCS in response to cisplatin induce an increase in the migration pattern of bone marrow MSCs (BM-MSCs) and the secretion interleukin-6 (IL-6), interleukin-8 (IL-8), and vascular endothelial growth factor A (VEGFA). Moreover, the factors secreted by BM-MSCs induce angiogenesis in endothelial cells and the migration of low-invasive ovarian cancer cells. These findings suggest that cisplatin could modulate the cargo of sEV released by CSCs, and these exosomes can further induce the pro-tumorigenic activity of MSCs.


Asunto(s)
Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Cisplatino/farmacología , Vesículas Extracelulares/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Neoplasias Ováricas/etiología , Neoplasias Ováricas/metabolismo , Línea Celular Tumoral , Citocinas/metabolismo , Exosomas/metabolismo , Exosomas/ultraestructura , Vesículas Extracelulares/ultraestructura , Femenino , Expresión Génica , Humanos , Metaloproteasas/genética , Metaloproteasas/metabolismo , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neoplasias Ováricas/patología , Esferoides Celulares , Microambiente Tumoral
14.
PLoS Genet ; 15(9): e1008415, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31568500

RESUMEN

Communication between neoplastic cells and cells of their microenvironment is critical to cancer progression. To investigate the role of cytoneme-mediated signaling as a mechanism for distributing growth factor signaling proteins between tumor and tumor-associated cells, we analyzed EGFR and RET Drosophila tumor models and tested several genetic loss-of-function conditions that impair cytoneme-mediated signaling. Neuroglian, capricious, Irk2, SCAR, and diaphanous are genes that cytonemes require during normal development. Neuroglian and Capricious are cell adhesion proteins, Irk2 is a potassium channel, and SCAR and Diaphanous are actin-binding proteins, and the only process to which they are known to contribute jointly is cytoneme-mediated signaling. We observed that diminished function of any one of these genes suppressed tumor growth and increased organism survival. We also noted that EGFR-expressing tumor discs have abnormally extensive tracheation (respiratory tubes) and ectopically express Branchless (Bnl, a FGF) and FGFR. Bnl is a known inducer of tracheation that signals by a cytoneme-mediated process in other contexts, and we determined that exogenous over-expression of dominant negative FGFR suppressed tumor growth. Our results are consistent with the idea that cytonemes move signaling proteins between tumor and stromal cells and that cytoneme-mediated signaling is required for tumor growth and malignancy.


Asunto(s)
Carcinogénesis/metabolismo , Transformación Celular Neoplásica/metabolismo , Seudópodos/fisiología , Animales , Carcinogénesis/genética , Estructuras de la Membrana Celular , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Receptores ErbB/metabolismo , Discos Imaginales/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Modelos Animales , Metástasis de la Neoplasia/genética , Neoplasias/metabolismo , Receptores de Péptidos de Invertebrados/metabolismo , Transducción de Señal/fisiología , Microambiente Tumoral/fisiología , Alas de Animales/crecimiento & desarrollo
15.
Int J Mol Sci ; 20(19)2019 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-31569731

RESUMEN

Epithelial-mesenchymal transition (EMT) is a process that takes place during embryonic development, wound healing, and under some pathological processes, including fibrosis and tumor progression. The molecular changes occurring within epithelial cells during transformation to a mesenchymal phenotype have been well studied. However, to date, the mechanism of EMT induction remains to be fully elucidated. Recent findings in the field of intercellular communication have shed new light on this process and indicate the need for further studies into this important mechanism. New evidence supports the hypothesis that intercellular communication between mesenchymal stroma/stem cells (MSCs) and resident epithelial cells plays an important role in EMT induction. Besides direct interactions between cells, indirect paracrine interactions by soluble factors and extracellular vesicles also occur. Extracellular vesicles (EVs) are important mediators of intercellular communication, through the transfer of biologically active molecules, genetic material (mRNA, microRNA, siRNA, DNA), and EMT inducers to the target cells, which are capable of reprogramming recipient cells. In this review, we discuss the role of intercellular communication by EVs to induce EMT and the acquisition of stemness properties by normal and tumor epithelial cells.


Asunto(s)
Transición Epitelial-Mesenquimal , Vesículas Extracelulares/metabolismo , Células Madre Mesenquimatosas/metabolismo , Animales , Comunicación Celular , Movimiento Celular , Transformación Celular Neoplásica/metabolismo , Humanos , Neoplasias/etiología , Neoplasias/metabolismo , Neoplasias/patología , Células Madre Neoplásicas/metabolismo
16.
Exp Oncol ; 41(3): 210-215, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31569933

RESUMEN

In this review, the role of nitric oxide (NO) in the pathogenesis of the tumor growth and possibilities of its application in the treatment of cancer patients are analyzed. NO is one of the most important mediators of physiological processes being involved in the regulation of practically all body functions in health and disease. The role of NO in the development of many pathological conditions has been extensively studied and debated in recent years. Today it is clear that NO in relation to malignant tumors may exhibit a dual activity - can stimulate tumor growth and cause an opposite antitumor effect. Effects of NO are mostly dependent on its concentration. At low concentrations, NO could inhibit apoptosis and cause mutations that potentially lead to the formation of malignant growth loci. However, a high concentration of NO appears to be detrimental to malignant cells, in particular under conditions of simultaneous exposure to ionizing radiation. In humans, the inducible NO synthase (iNOS, type II) is the most powerful form of NO synthases (NOS) and has the ability to synthesize large amounts of NO for a long time and exert a protective function. iNOS is expressed in macrophages, monocytes, neutrophils, fibroblasts, hepatocytes, and other cell types. In tissue of malignant tumors, the macrophagal iNOS is the main form. Experimental data provide an evidence that activated macrophages and leukocytes, which are the part of peritumorous inflammatory infiltrate, can provide radiosensitization of tumors by direct synthesis of NO and indirectly - through the secretion of cytokines stimulating iNOS activity in cancer cells. Such approach could be useful for the development of new schemes and methods of anticancer therapy based on the activation of endogenous NO biosynthesis pathways.


Asunto(s)
Transformación Celular Neoplásica/metabolismo , Neoplasias/etiología , Neoplasias/metabolismo , Óxido Nítrico/metabolismo , Animales , Biomarcadores , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Humanos , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias/patología , Neoplasias/terapia
17.
Exp Oncol ; 41(3): 216-223, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31569934

RESUMEN

Squamous cell carcinoma of the skin develops from the spectrum of facultative precancerous conditions, which in the course of malignant transformation through cancer stage in situ without early treatment fully transform into invasive squamous cell carcinoma. According to classical model of carcinogenesis, the transformation of actinic keratosis into squamous cell carcinoma of the skin occurs due to a mutation in one gene, more often a tumor suppressor, and undergoes a stage of development with lack of control of cell cycle. The aim of the research is to supplement current knowledge of genetic determination of pathogenetic mechanisms of epidermal dysplasia of the skin by studying the genetic determinant in the skin lesion of varying degrees of malignancy. MATERIALS AND METHODS: We analyzed 85 skin bioptates of patients with epidermal dysplasia of the skin (Gr 1 - 43 patients with actinic keratosis; Gr 2 - 21 patients with non-invasive squamous cell carcinoma of the skin; Gr 3 - 21 patients with invasive squamous cell carcinoma of the skin) by molecular genetic testing of gene polymorphisms: TP53 (G13494A), L-myc (T3109G), TNF-α (G308A) in tumor tissue. The histological examination revealed the levels of dysplasia of the epidermis. RESULTS: In case of the same disease duration in patients of Gr1/Gr3, L-myc (3109TT) is a genetic component of malignant transformation of epithelial skin cells (p = 0.004) and the development of invasive squamous cell carcinoma. Other variants of 3109TG and 3109GG genes do not have such prognostic value for the risk of skin cancer compared to 3109TT. Significant differences were found in the distribution of (13494GA) when comparing Gr 1 with Gr 3 (p = 0.014) and Gr 2 with Gr 3 (p = 0.038). A significant increase in the distribution of 13494GA genotype was revealed in patients with invasive form of keratinocyte intraepidermal neoplasia. 13494A allele was more likely to be detected in patients of Gr 3 compared to Gr 2 (p = 0.030) that proves the association of this allele with the development of invasive malignancies of the skin. The association of 308GG genotype and TNF-α (308G) allele with the development of malignant skin lesions was found. Comparing the distribution of 308G allele in patients of Gr 1 and Gr 2, we found its significant increase in patients of Gr 1. Comparative analysis of gene polymorphism with tumor invasion level showed a significant difference only in 308GG genotype between patients with grade III of KIN (keratinocyte intraepidermal neoplasia) in Gr 2 and patients with KIN III of Gr 1 (p = 0.007), and 308GA between patients with KIN III of Gr 2 and KIN III of Gr 1 (p = 0.027). CONCLUSIONS: Our work has supplemented modern vision of genetic component in pathogenetic mechanism of the development of epidermal dysplasia of the skin. Thus, the association of L-myc (3109TT) with the development of malignant skin lesions of different invasiveness and the modifying effect of TNF-α (G308A) and TP53 (G13494A) gene variants on pathological transformation in the focus of EDS depending on the level of epithelial dysplasia was revealed.


Asunto(s)
Transformación Celular Neoplásica , Queratosis Actínica/etiología , Queratosis Actínica/metabolismo , Anciano , Anciano de 80 o más Años , Alelos , Biopsia , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Epidermis/metabolismo , Epidermis/patología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Queratosis Actínica/patología , Queratosis Actínica/terapia , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Polimorfismo de Nucleótido Simple
18.
Exp Oncol ; 41(3): 200-206, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31569936

RESUMEN

The ORAI family of ion channel-forming proteins in mammals includes three members, ORAI1, ORAI2 and ORAI3, encoded by homologous genes. Of these proteins the ORAI1 one received major attention as plasma membrane constituent of store-operated calcium entry (SOCE) in non-excitable cells. The functional significance of two other proteins, ORAI2 and ORAI3, is much less defined, although both of them participate to various extends in cell-specific modulation of SOCE as well as in supporting some of the store-independent calcium entry mechanisms. Calcium signaling becomes remodeled in cancer to promote cancer hallmarks - enhanced proliferation, resistance to apoptosis, motility and metastasizing. Although such remodeling commonly involves rearrangements of the whole molecular Ca2+-handling toolkit of the cell (Ca2+ pumps and transporters, Ca2+-binding and storage proteins, Ca2+ entry and release channels, Ca2+-dependent effectors), Ca2+ entry through Orai-based channels is especially important, as its dysregulation may contribute to several cancer hallmarks. The latter depend on the type of Ca2+-permeable channel formed by ORAI-proteins, spatiotemporal characteristics of Ca2+ signal that this channel contributes to, and the type Ca2+-dependent effector(s) targeted by this signal, all of which may be cancer-specific. By participating in global Ca2+ entry, ORAI-based SOCE may also contribute to cytosolic Ca2+ overload of cancer cells thereby playing pro-apoptotic, antineoplastic roles which can potentially be exploited for cancer treatment. This mini review examines various aspects of ORAI proteins in malignant transformation.


Asunto(s)
Canales de Calcio Activados por la Liberación de Calcio/metabolismo , Calcio/metabolismo , Neoplasias/etiología , Neoplasias/metabolismo , Animales , Canales de Calcio Activados por la Liberación de Calcio/genética , Señalización del Calcio , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo
19.
Molecules ; 24(20)2019 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-31619002

RESUMEN

The prevalence of upper tract urothelial carcinoma (UTUC) in Taiwan is relatively higher than thatin Western countries. Aristolochic acid (AA), which is widely used in traditional Chinese herbology, is now recognized to be one of the carcinogens for UTUC. Numerous UTUC patients have chronic kidney diseases or end-stage renal diseases; however, little literature hasreported on theoncogenic pathway of AA-related UTUC. The aim of our study was to identify the potential target treatment for AA-related UTUC. Here, we established an AA pre-exposure followed bya 3-methylcholanthrene (MCA) stimulus tumorigenic cell model. We not only demonstrated that AA pre-exposure MCA stimulus tumorigenic cells have more behaviors of cell migration and invasion by enhancing the metalloproteinases (MMP) activity, which is compatible with clinical findings of AA-related UTUC, but we also validated that AA pre-exposure MCA stimulus tumorigeniccells could be activated through the mitogen-activated protein kinases (MAPK) pathway. We further dissected the route of the MAPK pathway and found that the p38 and extracellular signal regulated kinases (ERK) sub-pathways might play essential roles in AA pre-exposure urothelial cancer cell lines. This consequence was also corroborated with a tissue study in AA-exposed patients.


Asunto(s)
Ácidos Aristolóquicos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neoplasias Urológicas/metabolismo , Urotelio/metabolismo , Urotelio/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Humanos , Metaloproteinasas de la Matriz/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología
20.
Mol Cell ; 76(6): 872-884.e5, 2019 12 19.
Artículo en Inglés | MEDLINE | ID: mdl-31606273

RESUMEN

The Ras GTPases are frequently mutated in human cancer, and, although the Raf kinases are essential effectors of Ras signaling, the tumorigenic properties of specific Ras-Raf complexes are not well characterized. Here, we examine the ability of individual Ras and Raf proteins to interact in live cells using bioluminescence resonance energy transfer (BRET) technology. We find that C-Raf binds all mutant Ras proteins with high affinity, whereas B-Raf exhibits a striking preference for mutant K-Ras. This selectivity is mediated by the acidic, N-terminal segment of B-Raf and requires the K-Ras polybasic region for high-affinity binding. In addition, we find that C-Raf is critical for mutant H-Ras-driven signaling and that events stabilizing B-Raf/C-Raf dimerization, such as Raf inhibitor treatment or certain B-Raf mutations, can allow mutant H-Ras to engage B-Raf with increased affinity to promote tumorigenesis, thus revealing a previously unappreciated role for C-Raf in potentiating B-Raf function.


Asunto(s)
Proliferación Celular , Transformación Celular Neoplásica/metabolismo , Neoplasias/enzimología , Quinasas raf/metabolismo , Proteínas ras/metabolismo , Animales , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Células HeLa , Humanos , Masculino , Ratones , Mutación , Células 3T3 NIH , Neoplasias/genética , Neoplasias/patología , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Multimerización de Proteína , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas c-raf/genética , Proteínas Proto-Oncogénicas c-raf/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Transducción de Señal/genética , Esferoides Celulares , Quinasas raf/genética , Proteínas ras/genética
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