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1.
Cancer Sci ; 111(1): 36-46, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31705593

RESUMEN

Osteosarcoma (OS) is a highly malignant bone tumor and the prognosis for non-responders to chemotherapy remains poor. Previous studies have shown that human sarcomas contain sarcoma-initiating cells (SIC), which have the characteristics of high tumorigenesis and resistance to chemotherapy. In the present study, we characterized SIC of a novel OS cell line, screened for SIC-related genes, and tried to regulate the proliferation of OS by metabolic interference. Initially, we established a new human OS cell line (OS13) and isolated clones showing higher tumorigenesis as SIC (OSHIGH ) and counterpart clones. OSHIGH cells showed chemoresistance and their metabolism highly depended on aerobic glycolysis and suppressed oxidative phosphorylation. Using RNA-sequencing, we identified LIN28B as a SIC-related gene highly expressed in OSHIGH cells. mRNA of LIN28B was expressed in sarcoma cell lines including OS13, but its expression was not detectable in normal organs other than the testis and placenta. LIN28B protein was also detected in various sarcoma tissues. Knockdown of LIN28B in OS13 cells reduced tumorigenesis, decreased chemoresistance, and reversed oxidative phosphorylation function. Combination therapy consisting of a glycolysis inhibitor and low-dose chemotherapy had antitumor effects. In conclusion, manipulation of glycolysis combined with chemotherapy might be a good adjuvant treatment for OS. Development of immunotherapy targeting LIN28B, a so-called cancer/testis antigen, might be a good approach.


Asunto(s)
Neoplasias Óseas/genética , Glucólisis/genética , Osteosarcoma/genética , Proteínas de Unión al ARN/genética , Animales , Neoplasias Óseas/patología , Carcinogénesis/genética , Carcinogénesis/patología , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Osteosarcoma/patología , Fosforilación Oxidativa , Placenta/patología , Embarazo , Pronóstico , ARN Mensajero/genética , Testículo/patología
2.
Cancer Sci ; 111(1): 175-185, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31715070

RESUMEN

Neurogenic differentiation factor 1 (NeuroD1) is a transcription factor critical for promoting neuronal differentiation and maturation. NeuroD1 is involved in neuroblastoma and medulloblastoma; however, its molecular mechanism in promoting tumorigenesis remains unclear. Furthermore, the role of NeuroD1 in non-neural malignancies has not been widely characterized. Here, we found that NeuroD1 is highly expressed in colorectal cancer. NeuroD1-silencing induces the expression of p21, a master regulator of the cell cycle, leading to G2 -M phase arrest and suppression of colorectal cancer cell proliferation as well as colony formation potential. Moreover, NeuroD1-mediated regulation of p21 expression occurs in a p53-dependent manner. Through chromatin immunoprecipitation and point mutation analysis in the predicted NeuroD1 binding site of the p53 promoter, we found that NeuroD1 directly binds to the p53 promoter and suppresses its transcription, resulting in increased p53 expression in NeuroD1-silenced colorectal cancer cells. Finally, xenograft experiments demonstrated that NeuroD1-silencing suppresses colorectal cancer cell tumorigenesis potential by modulating p53 expression. These findings reveal NeuroD1 as a novel regulator of the p53/p21 axis, underscoring its importance in promoting non-neural malignancies. Furthermore, this study provides insight into the transcriptional regulation of p53.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Carcinogénesis/genética , Neoplasias Colorrectales/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Proteína p53 Supresora de Tumor/genética , Carcinogénesis/patología , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica/genética , Células HCT116 , Humanos , Neuroblastoma/genética , Neuroblastoma/patología , Regiones Promotoras Genéticas/genética , Factores de Transcripción/genética
3.
Cancer Sci ; 111(1): 137-147, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31724799

RESUMEN

As a member of the epidermal growth factor receptor (EGFR) family, ERBB3 plays an essential role in development and disease independent of inherently inactive kinase domain. Recently, ERBB3 has been found to bind to ATP and has catalytic activity in vitro. However, the biological function of ERBB3 kinase activity remains elusive in vivo. Here we have identified the physiological function of inactivated ERBB3 kinase activity by creating Erbb3-K740M knockin mice in which ATP cannot bind to ERBB3. Unlike Erbb3 knockout mice, kinase-inactive Erbb3K740M homozygous mice were born in Mendelian ratios and showed normal development. After dextran sulfate sodium-induced colitis, the kinase-inactive Erbb3 mutant mice showed normal recovery. However, the outgrowth of ileal organoids by neuregulin-1 treatment was more attenuated in Erbb3 mutant mice than in WT mice. Moreover, in combination with the ApcMin mouse, the proportion of polyps less than 1 mm in diameter in mutant mice was higher than in control mice and an increase in the number of apoptotic cells was observed in polyps from mutant mice compared with polyps from control mice. Taken together, the ERBB3 kinase activity contributes to the outgrowth of ileal organoids and intestinal tumorigenesis, and the development of ERBB3 kinase inhibitors, including epidermal growth factor receptor family members, can be a potential way to target colorectal cancer.


Asunto(s)
Carcinogénesis/metabolismo , Carcinogénesis/patología , Intestinos/patología , Organoides/metabolismo , Organoides/patología , Receptor ErbB-3/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Carcinogénesis/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Intestinos/efectos de los fármacos , Ratones , Ratones Noqueados , Organoides/efectos de los fármacos , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Pólipos/tratamiento farmacológico , Pólipos/patología , Inhibidores de Proteínas Quinasas/farmacología
4.
Gene ; 726: 144196, 2020 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-31669648

RESUMEN

Accumulating evidence has indicated the important roles of circular RNAs (circRNAs) in different tumors. However, their detailed regulatory mechanisms in glioma are not fully understood. In this study, the functional role of a novel circRNA, circ-EZH2, was investigated by cell counting kit-8 (CCK-8), colony formation, flow cytometry, and transwell experiments. The regulatory mechanism of circ-EZH2 was explored by bioinformatics analysis, quantitative real-time PCR (qRT-PCR), Western blot and dual-luciferase reporter assay. We identified that circ-EZH2 was overexpressed in glioma tissues and cell lines. Further studies revealed that ectopic expression of circ-EZH2 significantly promoted cell growth, migration and invasion but inhibited cell apoptosis. By contrast, silencing of circ-EZH2 induced the opposite effects. Additionally, we found circ-EZH2 served as a miRNA sponge for miR-1265 to release its suppression on DDAH1 and CBX3. Rescue assays further revealed that the oncogenic function of circ-EZH2 was partly dependent on its modulation of DDAH1 and CBX3. Our study unraveled a novel molecular pathway in glioma and may provide a new perspective for the treatment of glioma.


Asunto(s)
Amidohidrolasas/genética , Proliferación Celular/genética , Proteínas Cromosómicas no Histona/genética , Proteína Potenciadora del Homólogo Zeste 2/genética , Glioma/genética , MicroARNs/genética , Invasividad Neoplásica/genética , Apoptosis/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Carcinogénesis/genética , Carcinogénesis/patología , Línea Celular Tumoral , Movimiento Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Glioma/patología , Humanos , Invasividad Neoplásica/patología
5.
Adv Exp Med Biol ; 1131: 605-623, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31646527

RESUMEN

Transient receptor potential (TRP) cation channel superfamily plays important roles in a variety of cellular processes such polymodal cellular sensing, adhesion, polarity, proliferation, differentiation and apoptosis. The expression of TRP channels is strictly regulated and their de-regulation can stimulate cancer development and progression.In human cancers, specific miRNAs are expressed in different tissues, and changes in the regulation of gene expression mediated by specific miRNAs have been associated with carcinogenesis. Several miRNAs/TRP channel pairs have been reported to play an important role in tumor biology. Thus, the TRPM1 gene regulates melanocyte/melanoma behaviour via TRPM1 and microRNA-211 transcripts. Both miR-211 and TRPM1 proteins are regulated through microphthalmia-associated transcription factor (MIFT) and the expression of miR-211 is decreased during melanoma progression. Melanocyte phenotype and melanoma behaviour strictly depend on dual TRPM1 activity, with loss of TRPM1 protein promoting melanoma aggressiveness and miR-211 expression supporting tumour suppressor. TRPM3 plays a major role in the development and progression of human clear cell renal cell carcinoma (ccRCC) with von Hippel-Lindau (VHL) loss. TRPM3, a direct target of miR-204, is enhanced in ccRCC with inactivated or deleted VHL. Loss of VHL inhibits miR-204 expression that lead to increased oncogenic autophagy. Therefore, the understanding of specific TRP channels/miRNAs molecular pathways in distinct tumors could provide a clinical rationale for target therapy in cancer.


Asunto(s)
Carcinogénesis , Regulación Neoplásica de la Expresión Génica , MicroARNs , Neoplasias , Canales Receptores Transitorios de Potencial , Carcinogénesis/genética , Carcinogénesis/patología , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias/fisiopatología , Canales Receptores Transitorios de Potencial/genética , Canales Receptores Transitorios de Potencial/metabolismo
6.
Int J Nanomedicine ; 14: 6465-6480, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31616140

RESUMEN

Purpose: Multiwalled carbon nanotubes (MWCNTs) have been known to enter the circulatory system via the lungs from inhalation exposure; however, its carcinogenicity and subsequent accumulation in other organs have not been adequately reported in the literature. Moreover, the safety of MWCNTs as a biomaterial has remained a matter of debate, particularly when the material enters the circulatory system. To address these problems, we used carcinogenic rasH2 transgenic mice to intravenously administer highly dispersed MWCNTs and to evaluate their carcinogenicity and accumulation in the organs. Methods: Two types of MWCNTs (thin- and thick-MWCNTs) were intravenously administered at a high dose (approximately 0.7 mg per kg body weight) and low dose (approximately 0.07 mg per kg body weight). Results: MWCNTs showed pancreatic accumulation in 3.2% of mice administered with MWCNTs, but there was no accumulation in other organs. In addition, there was no significant difference in the incidence of tumor among the four MWCNTs-administered groups compared to the vehicle group without MWCNTs administration. Blood tests revealed elevated levels in mean red blood cell volume and mean red blood cell hemoglobin level for the MWCNTs-administered group, in addition to an increase in eotaxin. Conclusion: The present study demonstrated that the use of current technology to sufficiently disperse MWCNTs resulted in minimal organ accumulation with no evidence of carcinogenicity.


Asunto(s)
Carcinógenos/toxicidad , Nanotubos de Carbono/toxicidad , Administración Intravenosa , Animales , Peso Corporal , Carcinogénesis/patología , Citocinas/metabolismo , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Ratones Transgénicos , Nanotubos de Carbono/ultraestructura , Análisis de Supervivencia , Distribución Tisular/efectos de los fármacos
7.
Life Sci ; 238: 116968, 2019 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-31628914

RESUMEN

AIMS: Colorectal cancer (CRC) is the third most common cancer worldwide. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of many cytoprotective genes, plays a protective role in carcinogenesis. Recent studies have identified a specific gene-expression signature regulated by the Nrf2 pathway in lung adenocarcinoma and head-and-neck squamous cell cancer. However, the roles of Nrf2 in the development of colitis-associated colorectal cancer (CACC) have not been well characterized. Nrf2 target genes as prognostic biomarkers in CACC remain to be explored. Thus, this work aimed to identify the molecular changes that occur during mouse CACC progression to facilitate the development of diagnostic and prognostic biomarkers. MAIN METHODS: The CACC model was established using azoxymethane (AOM) with dextran sulfate sodium salt (DSS) in BALB/c mice for 3 weeks to induce colitis-associated adenoma (CAA, early stage) and for 9 weeks to induce colitis-associated carcinoma (CAC, late stage). Using RNA-sequencing and bioinformatics analyses we examined the mRNA expression profiles of 6 groups: wild-type control (WT-C), WT-CAA, WT-CAC, Nrf2 knockout control (Nrf2KO-C), Nrf2KO-CAA, and Nrf2KO-CAC. KEY FINDINGS: In the AOM/DSS model of colitis-associated tumorigenesis, Nrf2-/- mice showed a phenotype similar to WT mice, but with significantly more tumors and a much higher percentage of adenocarcinomas. We identified 47 novel Nrf2 genes via gene expression profiling of tumor samples. Survival analysis showed that 23 of these genes were biomarkers of a poor prognosis in colon cancer patients. SIGNIFICANCE: Nrf2 target genes deserve exploration as prognostic and therapeutic targets for CRC.


Asunto(s)
Biomarcadores/metabolismo , Carcinogénesis/patología , Colitis/complicaciones , Neoplasias Colorrectales/diagnóstico , Regulación Neoplásica de la Expresión Génica , Factor 2 Relacionado con NF-E2/fisiología , Animales , Azoximetano/toxicidad , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinógenos/toxicidad , Colitis/inducido químicamente , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/metabolismo , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal
8.
Life Sci ; 236: 116918, 2019 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-31610208

RESUMEN

Long noncoding RNAs (lncRNAs) are characterized as a group of endogenous RNAs that are more than 200 nucleotides in length and have no protein-encoding function. More and more evidence indicates that lncRNAs play vital roles in various human diseases, especially in tumorigenesis. Focally amplified lncRNA on chromosome 1 (FAL1), a novel lncRNA with enhancer-like activity, has been identified as an oncogene in multiple cancers and high expression level of FAL1 is usually associated with poor prognosis. Dysregulation of FAL1 has been shown to promote the proliferation and metastasis of cancer cells. In the present review, we summarized and illustrated the functions and underlying molecular mechanisms of FAL1 in the occurrence and development of different cancers and other diseases. FAL1 has the potential to appear as a feasible diagnostic and prognostic tool and new therapeutic target for cancer patients though further investigation is needed so as to accelerate clinical application.


Asunto(s)
Carcinogénesis/genética , Carcinogénesis/patología , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Neoplasias/patología , ARN Largo no Codificante/genética , Humanos , Transducción de Señal
9.
Adv Exp Med Biol ; 1164: 73-87, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31576541

RESUMEN

The purpose of this review is to briefly summarize the roles of alcohol (ethanol) and related compounds in promoting cancer and inflammatory injury in many tissues. Long-term chronic heavy alcohol exposure is known to increase the chances of inflammation, oxidative DNA damage, and cancer development in many organs. The rates of alcohol-mediated organ damage and cancer risks are significantly elevated in the presence of co-morbidity factors such as poor nutrition, unhealthy diets, smoking, infection with bacteria or viruses, and exposure to pro-carcinogens. Chronic ingestion of alcohol and its metabolite acetaldehyde may initiate and/or promote the development of cancer in the liver, oral cavity, esophagus, stomach, gastrointestinal tract, pancreas, prostate, and female breast. In this chapter, we summarize the important roles of ethanol/acetaldehyde in promoting inflammatory injury and carcinogenesis in several tissues. We also review the updated roles of the ethanol-inducible cytochrome P450-2E1 (CYP2E1) and other cytochrome P450 isozymes in the metabolism of various potentially toxic substrates, and consequent toxicities, including carcinogenesis in different tissues. We also briefly describe the potential implications of endogenous ethanol produced by gut bacteria, as frequently observed in the experimental models and patients of nonalcoholic fatty liver disease, in promoting DNA mutation and cancer development in the liver and other tissues, including the gastrointestinal tract.


Asunto(s)
Trastornos Relacionados con Alcohol , Carcinogénesis , Citocromo P-450 CYP2E1 , Sistema Enzimático del Citocromo P-450 , Etanol , Acetaldehído/toxicidad , Trastornos Relacionados con Alcohol/fisiopatología , Carcinogénesis/efectos de los fármacos , Carcinogénesis/patología , Citocromo P-450 CYP2E1/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Etanol/toxicidad , Humanos , Isoformas de Proteínas
10.
Anticancer Res ; 39(10): 5789-5795, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31570483

RESUMEN

BACKGROUND/AIM: Pulmonary pleomorphic carcinoma (PPC) is rare, and few studies have reported its features. We assessed the clinicopathological features, surgical outcomes, oncogenic status and programmed death-ligand 1 (PD-L1) expression of PPC. PATIENTS AND METHODS: We retrospectively reviewed data from 22 consecutive patients who underwent resection of PPC between 2007 and 2017. RESULTS: The predominant tissue type of the epithelial component was adenocarcinoma in 15 patients (68%) and the others in 7 patients (32%), and the 3-year disease-free survival rate tended to be better in patients with an adenocarcinoma component compared to patients with another component (40.0% vs. 17.1%, p=0.059). PD-L1 expression was observed in all eight tumors whose PD-L1 status could be examined and high PD-L1 expression (≥50%) was frequent (5/8, 63%). CONCLUSION: A predominant adenocarcinoma epithelial component in PPC might be associated with better survival outcomes and high PD-L1 expression might be frequent in PPC.


Asunto(s)
Antígeno B7-H1/genética , Carcinoma/genética , Carcinoma/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Oncogenes/genética , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Carcinogénesis/genética , Carcinogénesis/patología , Carcinoma/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia
11.
Int J Nanomedicine ; 14: 7107-7121, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31564868

RESUMEN

Background: Cervical cancer (CxCa) ranks as the fourth most prevalent women-related cancer worldwide. Therefore, there is a crucial need to develop newer treatment modalities. Ormeloxifene (ORM) is a non-steroidal, selective estrogen receptor modulator (SERM) that is used as an oral contraceptive in humans. Recent investigations suggest that ORM exhibits potent anti-cancer activity against various types of cancers. Nanoparticulates offer targeted delivery of anti-cancer drugs with minimal toxicity and promise newer approaches for cancer diagnosis and treatment. Therefore, the nanotherapy approach is superior compared to traditional chemotherapy, which is not site-specific and is often associated with various side effects. Methods: Pursuing this novel nanotherapy approach, our lab has recently developed ORM-loaded poly [lactic-co-glycolic acid] (PLGA), an FDA-approved biodegradable polymer, nanoparticles to achieve targeted drug delivery and improved bioavailability. Our optimized PLGA-ORM nanoformulation showed improved internalization in both dose- and energy-dependent manners, through endocytosis-mediated pathways in both Caski and SiHa cell lines. Additionally, we employed MTS and colony forming assays to determine the short- and long-term effects of PLGA-ORM on these cells. Results: Our results showed that this formulation demonstrated improved inhibition of cellular proliferation and clonogenic potential compared to free ORM. Furthermore, the PLGA-ORM nanoformulation exhibited superior anti-tumor activities in an orthotopic cervical cancer mouse model than free ORM. Conclusion: Collectively, our findings suggest that our novel nanoformulation has great potential for repurposing the drug and becoming a novel modality for CxCa management.


Asunto(s)
Benzopiranos/uso terapéutico , Nanopartículas/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Animales , Benzopiranos/farmacología , Carcinogénesis/efectos de los fármacos , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Clonales , Modelos Animales de Enfermedad , Endocitosis/efectos de los fármacos , Eritrocitos/metabolismo , Femenino , Hemólisis/efectos de los fármacos , Humanos , Ensayo de Materiales , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Desnudos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Suero/química , Neoplasias del Cuello Uterino/patología
12.
Life Sci ; 238: 116977, 2019 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-31639400

RESUMEN

AIMS: In the cell, both transcriptional and translational processes are tightly regulated. Cancer is a multifactorial disease characterized by aberrant protein expression. Since epigenetic control mechanisms are also frequently disrupted during carcinogenesis, they have been the center of attention in cancer research within the past decades. EEF1 complex members, which are required for the elongation process in eukaryotes, have recently been implicated in carcinogenesis. This study aims to investigate genetic alterations within EEF1A1, EEF1A2, EEF1B2, EEF1D, EEF1E1 and EEF1G genes and their potential effects on epigenetic regulation mechanisms. MATERIALS AND METHODS: In this study, we analyzed DNA sequencing and mRNA expression data available on The Cancer Genome Atlas (TCGA) across different cancer types to detect genetic alterations in EEF1 genes and investigated their potential impact on selected epigenetic modulators. KEY FINDINGS: We found that EEF1 complex proteins were deregulated in several types of cancer. Lower EEF1A1, EEF1B2, EEF1D and EEF1G levels were correlated with poor survival in glioma, while lower EEF1B2, EEF1D and EEF1E1 levels were correlated with better survival in hepatocellular carcinoma. We detected genetic alterations within EEF1 genes in up to 35% of the patients and showed that these alterations resulted in down-regulation of histone modifying enzymes KMT2C, KMT2D, KMT2E, KAT6A and EP300. SIGNIFICANCE: Here in this study, we showed that EEF1 deregulations might result in differential epigenomic landscapes, which affect the overall transcriptional profile, contributing to carcinogenesis. Identification of these molecular distinctions might be useful in developing targeted drug therapies and personalized medicine.


Asunto(s)
Biomarcadores de Tumor/genética , Carcinogénesis/patología , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Neoplasias/patología , Factor 1 de Elongación Peptídica/genética , Carcinogénesis/metabolismo , Redes Reguladoras de Genes , Factores de Intercambio de Guanina Nucleótido/genética , Humanos , Factores de Elongación de Péptidos/genética , Proteínas Supresoras de Tumor/genética
13.
Int J Nanomedicine ; 14: 7963-7973, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31632011

RESUMEN

Background: Amphiphilic fusion drugs are covalent conjugates of a lipophilic drug and a hydrophilic drug or their active fragments. These carrier-free self-assembly nanomaterials are helpful to co-deliver two synergic drugs to the same site regardless of pharmacokinetic properties of individual drugs. Retinoic hydroxamic acid (RHA) is a "fusion drug" of all-trans retinoic acid (ATRA) and vorinostat, a histone deacetylase (HDAC) inhibitor showing synergic effect with ATRA on cancer therapy. Although RHA was synthesized in 2005, its nanoscale self-assembly property, anticancer activity, and possible related mechanism are still unclear. Methods: RHA nanoparticles were observed under transmission electron microscope (TEM). Both in vitro cell viability, colony formation assay, and in vivo xenograft mouse tumor model were employed here to study anticancer activity of RHA nanoparticles. The putative synergic anticancer mechanism of activating retinoic acid receptor (RAR) and inhibiting HDAC were investigated via receptor inhibitor rescue assay and in vitro enzyme activity assay, respectively. Results: RHA could form nanoparticle formation by self-assembly and abrogates growth of several solid tumor cell lines even after RHA nanoparticles' washout. However, opposite to our initial hypothesis, pre-treating the melanoma cells with RAR antagonists showed no impact on inhibitory effect of RHA nanoparticles, which suggested that the target of the molecule on melanoma cells is not RAR and retinoid X receptor (RXR). Importantly, RHA nanoparticles inhibited the growth of xenograft tumors without obvious impact on haematological indexes and hepatorenal function of these tumor-bearing mice. Conclusion: Our findings demonstrate the promise of RHA nanoparticles in treating malignant melanoma tumors with high efficacy and low toxicity.


Asunto(s)
Melanoma/tratamiento farmacológico , Nanopartículas/química , Retinoides/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Carcinogénesis/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Melanoma/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/ultraestructura , Tamaño de la Partícula , Retinoides/farmacología
14.
Nat Commun ; 10(1): 4123, 2019 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-31511511

RESUMEN

In adult epithelial stem cell lineages, the precise differentiation of daughter cells is critical to maintain tissue homeostasis. Notch signaling controls the choice between absorptive and entero-endocrine cell differentiation in both the mammalian small intestine and the Drosophila midgut, yet how Notch promotes lineage restriction remains unclear. Here, we describe a role for the transcription factor Klumpfuss (Klu) in restricting the fate of enteroblasts (EBs) in the Drosophila intestine. Klu is induced in Notch-positive EBs and its activity restricts cell fate towards the enterocyte (EC) lineage. Transcriptomics and DamID profiling show that Klu suppresses enteroendocrine (EE) fate by repressing the action of the proneural gene Scute, which is essential for EE differentiation. Loss of Klu results in differentiation of EBs into EE cells. Our findings provide mechanistic insight into how lineage commitment in progenitor cell differentiation can be ensured downstream of initial specification cues.


Asunto(s)
Linaje de la Célula , Proteínas de Unión al ADN/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citología , Enterocitos/citología , Intestinos/citología , Células Madre/citología , Factores de Transcripción/metabolismo , Animales , Carcinogénesis/metabolismo , Carcinogénesis/patología , Diferenciación Celular , Proliferación Celular , Modelos Biológicos , Unión Proteica , Receptores Notch/metabolismo , Transducción de Señal , Células Madre/metabolismo
15.
Nat Commun ; 10(1): 4108, 2019 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-31511525

RESUMEN

Recent advance in cancer research sheds light on the contribution of mitochondrial respiration in tumorigenesis, as they efficiently produce ATP and oncogenic metabolites that will facilitate cancer cell growth. Here we show that a stabilizing factor for mitochondrial supercomplex assembly, COX7RP/COX7A2L/SCAF1, is abundantly expressed in clinical breast and endometrial cancers. Moreover, COX7RP overexpression associates with prognosis of breast cancer patients. We demonstrate that COX7RP overexpression in breast and endometrial cancer cells promotes in vitro and in vivo growth, stabilizes mitochondrial supercomplex assembly even in hypoxic states, and increases hypoxia tolerance. Metabolomic analyses reveal that COX7RP overexpression modulates the metabolic profile of cancer cells, particularly the steady-state levels of tricarboxylic acid cycle intermediates. Notably, silencing of each subunit of the 2-oxoglutarate dehydrogenase complex decreases the COX7RP-stimulated cancer cell growth. Our results indicate that COX7RP is a growth-regulatory factor for breast and endometrial cancer cells by regulating metabolic pathways and energy production.


Asunto(s)
Neoplasias de la Mama/patología , Carcinogénesis/patología , Neoplasias Endometriales/metabolismo , Hipoxia/patología , Mitocondrias/metabolismo , Neoplasias de la Mama/genética , Carcinogénesis/metabolismo , Línea Celular Tumoral , Proliferación Celular , Complejo IV de Transporte de Electrones/metabolismo , Neoplasias Endometriales/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Hipoxia/metabolismo , Complejo Cetoglutarato Deshidrogenasa/metabolismo , Consumo de Oxígeno , Especies Reactivas de Oxígeno/metabolismo
16.
Nat Commun ; 10(1): 4255, 2019 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-31534141

RESUMEN

Caspase-10 belongs to the class of initiator caspases and is a close homolog of caspase-8. However, the lack of caspase-10 in mice and limited substrate repertoire restricts the understanding of its physiological functions. Here, we report that ATP-citrate lyase (ACLY) is a caspase-10 substrate. Caspase-10 cleaves ACLY at the conserved Asp1026 site under conditions of altered metabolic homeostasis. Cleavage of ACLY abrogates its enzymatic activity and suppresses the generation of acetyl-CoA, which is critical for lipogenesis and histone acetylation. Thus, caspase-10-mediated ACLY cleavage results in reduced intracellular lipid levels and represses GCN5-mediated histone H3 and H4 acetylation. Furthermore, decline in GCN5 activity alters the epigenetic profile, resulting in downregulation of proliferative and metastatic genes. Thus caspase-10 suppresses ACLY-promoted malignant phenotype. These findings expand the substrate repertoire of caspase-10 and highlight its pivotal role in inhibiting tumorigenesis through metabolic and epigenetic mechanisms.


Asunto(s)
ATP Citrato (pro-S)-Liasa/antagonistas & inhibidores , Carcinogénesis/patología , Caspasa 10/metabolismo , Epigénesis Genética/genética , Neoplasias/patología , Células A549 , Acetilcoenzima A/biosíntesis , Acetilación , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Células HCT116 , Células HEK293 , Histonas/metabolismo , Humanos , Lipogénesis/fisiología , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Trasplante Heterólogo , Factores de Transcripción p300-CBP/metabolismo
17.
Nat Commun ; 10(1): 4258, 2019 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-31534142

RESUMEN

The human genome is folded into regulatory units termed 'topologically-associated domains' (TADs). Genome-wide studies support a global role for the insulator protein CTCF in mediating chromosomal looping and the topological constraint of TAD boundaries. However, the impact of individual insulators on enhancer-gene interactions and transcription remains poorly understood. Here, we investigate epigenome editing strategies for perturbing individual CTCF insulators and evaluating consequent effects on genome topology and transcription. We show that fusions of catalytically-inactive Cas9 (dCas9) to transcriptional repressors (dCas9-KRAB) and DNA methyltransferases (dCas9-DNMT3A, dCas9-DNMT3A3L) can selectively displace CTCF from specific insulators, but only when precisely targeted to the cognate motif. We further demonstrate that stable, partially-heritable insulator disruption can be achieved through combinatorial hit-and-run epigenome editing. Finally, we apply these strategies to simulate an insulator loss mechanism implicated in brain tumorigenesis. Our study provides strategies for stably modifying genome organization and gene activity without altering the underlying DNA sequence.


Asunto(s)
Factor de Unión a CCCTC/genética , Proteína 9 Asociada a CRISPR/genética , Carcinogénesis/genética , ADN (Citosina-5-)-Metiltransferasas/genética , Edición Génica/métodos , Proteínas Recombinantes de Fusión/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Sistemas CRISPR-Cas/genética , Carcinogénesis/patología , Línea Celular , Metilación de ADN , Epigénesis Genética/genética , Genoma Humano/genética , Células HEK293 , Humanos , Regiones Promotoras Genéticas/genética , Proteínas Represoras/metabolismo
18.
EMBO J ; 38(20): e102096, 2019 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-31483066

RESUMEN

Engineered p53 mutant mice are valuable tools for delineating p53 functions in tumor suppression and cancer therapy. Here, we have introduced the R178E mutation into the Trp53 gene of mice to specifically ablate the cooperative nature of p53 DNA binding. Trp53R178E mice show no detectable target gene regulation and, at first sight, are largely indistinguishable from Trp53-/- mice. Surprisingly, stabilization of p53R178E in Mdm2-/- mice nevertheless triggers extensive apoptosis, indicative of residual wild-type activities. Although this apoptotic activity suffices to trigger lethality of Trp53R178E ;Mdm2-/- embryos, it proves insufficient for suppression of spontaneous and oncogene-driven tumorigenesis. Trp53R178E mice develop tumors indistinguishably from Trp53-/- mice and tumors retain and even stabilize the p53R178E protein, further attesting to the lack of significant tumor suppressor activity. However, Trp53R178E tumors exhibit remarkably better chemotherapy responses than Trp53-/- ones, resulting in enhanced eradication of p53-mutated tumor cells. Together, this provides genetic proof-of-principle evidence that a p53 mutant can be highly tumorigenic and yet retain apoptotic activity which provides a survival benefit in the context of cancer therapy.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Leucemia Mieloide Aguda/prevención & control , Linfoma/prevención & control , Mutación , Proteínas Proto-Oncogénicas c-mdm2/fisiología , Proteína p53 Supresora de Tumor/fisiología , Animales , Carcinogénesis/efectos de los fármacos , Carcinogénesis/metabolismo , Carcinogénesis/patología , Ciclo Celular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Linfoma/genética , Linfoma/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Tumorales Cultivadas
19.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 48(3): 318-325, 2019 May 25.
Artículo en Chino | MEDLINE | ID: mdl-31496165

RESUMEN

Proteins are the physical basis of life and perform all kinds of life activities. Proteins have different orientations and function in different tissues. The same protein, located in different subcellular regions, can perform different and even opposite functions. Both functional and structural proteins are capable of undergoing re-localization which can directly or indirectly participate in signal transduction. Due to abnormal transduction of signals during carcinogenesis, the proteins originally expressed in the cytoplasm are translocated into the nucleus and lead to functional changes in the tumor tissue. The changes of protein localization are affected by many factors, including the interaction between proteins, expression level of proteins and the cleaved intracellular domain of transmembrane protein.


Asunto(s)
Núcleo Celular , Citoplasma , Proteínas de la Membrana , Carcinogénesis/patología , Línea Celular Tumoral , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de la Membrana/metabolismo , Dominios Proteicos , Transporte de Proteínas/fisiología , Transducción de Señal
20.
Int J Mol Sci ; 20(17)2019 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-31480221

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is responsible for 7.3% of all cancer deaths. Even though there is a steady increase in patient survival for most cancers over the decades, the patient survival rate for pancreatic cancer remains low with current therapeutic strategies. The Wnt/ß-catenin pathway controls the maintenance of somatic stem cells in many tissues and organs and is implicated in pancreatic carcinogenesis by regulating cell cycle progression, apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, tumor immune microenvironment, etc. Further, dysregulated Wnt has been shown to cause drug resistance in pancreatic cancer. Although different Wnt antagonists are effective in pancreatic patients, limitations remain that must be overcome to increase the survival benefits associated with this emerging therapy. In this review, we have summarized the role of Wnt signaling in pancreatic cancer and suggested future directions to enhance the survival of pancreatic cancer patients.


Asunto(s)
Carcinogénesis/metabolismo , Carcinogénesis/patología , Resistencia a Antineoplásicos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Vía de Señalización Wnt , Animales , Humanos , Modelos Biológicos , Terapia Molecular Dirigida
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