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Some citrus orchards in China often experience nitrogen (N) deficiency. For the first time, targeted metabolomics was used to examine N-deficient effects on hormones in sweet orange (Citrus sinensis (L.) Osbeck cv. Xuegan) leaves and roots. The purpose was to validate the hypothesis that hormones play a role in N deficiency tolerance by regulating root/shoot dry weight ratio (R/S), root system architecture (RSA), and leaf and root senescence. N deficiency-induced decreases in gibberellins and indole-3-acetic acid (IAA) levels and increases in cis(+)-12-oxophytodienoic acid (OPDA) levels, ethylene production, and salicylic acid (SA) biosynthesis might contribute to reduced growth and accelerated senescence in leaves. The increased ethylene formation in N-deficient leaves might be caused by increased 1-aminocyclopropanecarboxylic acid and OPDA and decreased abscisic acid (ABA). N deficiency increased R/S, altered RSA, and delayed root senescence by lowering cytokinins, jasmonic acid, OPDA, and ABA levels and ethylene and SA biosynthesis, increasing 5-deoxystrigol levels, and maintaining IAA and gibberellin homeostasis. The unchanged IAA concentration in N-deficient roots involved increased leaf-to-root IAA transport. The different responses of leaf and root hormones to N deficiency might be involved in the regulation of R/S, RSA, and leaf and root senescence, thus improving N use efficiency, N remobilization efficiency, and the ability to acquire N, and hence conferring N deficiency tolerance.
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Circadian homeostasis in mammals is a key intrinsic mechanism for responding to the external environment. However, the interplay between circadian rhythms and the tumor microenvironment (TME) and its influence on metastasis are still unclear. Here, in patients with colorectal cancer (CRC), disturbances of circadian rhythm and the accumulation of monocytes and granulocytes were closely related to metastasis. Moreover, dysregulation of circadian rhythm promoted lung metastasis of CRC by inducing the accumulation of myeloid-derived suppressor cells (MDSCs) and dysfunctional CD8+ T cells in the lungs of mice. Also, gut microbiota and its derived metabolite taurocholic acid (TCA) contributed to lung metastasis of CRC by triggering the accumulation of MDSCs in mice. Mechanistically, TCA promoted glycolysis of MDSCs epigenetically by enhancing mono-methylation of H3K4 of target genes and inhibited CHIP-mediated ubiquitination of PDL1. Our study links the biological clock with MDSCs in the TME through gut microbiota/metabolites in controlling the metastatic spread of CRC, uncovering a systemic mechanism for cancer metastasis.
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Relojes Circadianos , Microbioma Gastrointestinal , Células Supresoras de Origen Mieloide , Animales , Ratones , Células Supresoras de Origen Mieloide/metabolismo , Humanos , Metástasis de la Neoplasia , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/microbiología , Ratones Endogámicos C57BL , Masculino , Microambiente Tumoral , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/metabolismo , Femenino , Ratones Endogámicos BALB C , Línea Celular TumoralRESUMEN
Background: Esophageal carcinoma accompanied by a right aortic arch (RAA) is very rare. When combined with Kommerell diverticulum (KD), a right aortic arch forms a vascular ring encircling both the esophagus and trachea. Due to abnormal anatomy of the upper mediastinum, it is very difficult to dissociate the esophagus and its surrounding tissues, especially the left recurrent laryngeal nerve. Herein, we report a case of successful thoracoscopic esophagectomy in an esophageal cancer patient concurrent with a RAA and KD. Case presentation: A 62-year-old male patient was diagnosed with esophageal squamous carcinoma in the middle esophagus at clinical stage I (cT1N0M0) according to UICC-TNM classification 8th edition. Further examinations revealed RAA and KD. Based on the three-dimensional CT (3D-CT) reconstruction, a Mckeown esophagectomy via a left thoracoscopic approach in semi-prone position was performed. During the operation, the left recurrent laryngeal nerve was accurately exposed and well protected. Postoperatively, severe complications, including anastomotic leakage and recurrent laryngeal nerve palsy, were not observed. The patient was discharged 12 days after the surgery. Conclusion: Preoperative 3D-CT reconstruction is useful to clarify the vascular malformation in esophageal cancer patients with RAA, and helpful to formulate a reasonable surgical approach.
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Boron (B) can alleviate Citrus copper (Cu)-toxicity. However, the underlying mechanism by which B mitigates Cu-toxicity is unclear. 'Xuegan' (Citrus sinensis) seedlings were exposed to 0.5 (control) or 350 (Cu-toxicity) µM Cu and 2.5 or 25 µM B for 24 weeks. Thereafter, we investigated the secretion of low molecular weight compounds [LMWCs; citrate, malate, total soluble sugars (TSS), total phenolics (TP), and total free amino acids (TFAA)] by excised roots and their concentrations in roots and leaves, as well as related enzyme gene expression and activities in roots and leaves. Cu-stress stimulated root release of malate and TFAA, which might contribute to citrus Cu-tolerance. However, B-mediated-mitigation of Cu-stress could not be explained in this way, since B addition failed to further stimulate malate and TFAA secretion. Indeed, B addition decreased Cu-stimulated-secretion of malate. Further analysis suggested that Cu-induced-exudation of malate and TFAA was not regulated by their levels in roots. By contrast, B addition increased malate, citrate, and TFAA concentrations in Cu-toxic roots. Cu-toxicity increased TP concentration in 25 µM B-treated leaves, but not in 2.5 µM B-treated leaves. Our findings suggested that the internal detoxification of Cu by LMWCs played a role in B-mediated-alleviation of Cu-toxicity.
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Citrus sinensis , Boro/toxicidad , Cobre/toxicidad , Malatos , Plantones/genética , Aminoácidos , Citratos , Ácido Cítrico , Exudados y Transudados , Fenoles , Expresión GénicaRESUMEN
Citrus sinensis seedlings were supplied with a nutrient solution containing 15 (control) or 0 (nitrogen (N) deficiency) mM N for 10 weeks. Extensive metabolic and gene reprogramming occurred in 0 mM N-treated roots (RN0) to cope with N deficiency, including: (a) enhancing the ability to keep phosphate homeostasis by elevating the abundances of metabolites containing phosphorus and the compartmentation of phosphate in plastids, and/or downregulating low-phosphate-inducible genes; (b) improving the ability to keep N homeostasis by lowering the levels of metabolites containing N but not phosphorus, upregulating N compound degradation, the root/shoot ratio, and the expression of genes involved in N uptake, and resulting in transitions from N-rich alkaloids to carbon (C)-rich phenylpropanoids and phenolic compounds (excluding indole alkaloids) and from N-rich amino acids to C-rich carbohydrates and organic acids; (c) upregulating the ability to maintain energy homeostasis by increasing energy production (tricarboxylic acid cycle, glycolysis/gluconeogenesis, oxidative phosphorylation, and ATP biosynthetic process) and decreasing energy utilization for amino acid and protein biosynthesis and new root building; (d) elevating the transmembrane transport of metabolites, thus enhancing the remobilization and recycling of useful compounds; and (e) activating protein processing in the endoplasmic reticulum. RN0 had a higher ability to detoxify reactive oxygen species and aldehydes, thus protecting RN0 against oxidative injury and delaying root senescence.
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Scorpiothyrsus erythrotrichus belongs to Melastomataceae. Here, we present its complete plastome. To our knowledge, this is the first reported complete chloroplast genome of S. erythrotrichus. The complete plastome of S. erythrotrichus is 160,731 bp in length with a typical quadripartite structure, consisting of four regions: large single-copy (LSC) region (85,483 bp), small single-copy (SSC) region (17,007 bp), and two inverted repeat regions (IRs, 26,780 bp). It contains 128 genes (79 coding genes, four rRNAs, and 30 tRNAs). The overall GC content is 36.9% and in the LSC, SSC, and IR regions are 34.70%, 30.40%, and 42.50%, respectively. Our study contributes to the molecular phylogenetic studies of Scorpiothyrsus and Melastomataceae.
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Circular RNA is a newly discovered member of non-coding RNA (ncRNA) and regulates the target gene by acting as a micro-RNA sponge. It plays vital roles in various diseases. However, the functions of circular RNA in non-small cell lung cancer (NSCLC) remain still unclear. Our data showed that circ-WHSC1 was highly expressed in NSCLC cells and tissues. Both in vitro and in vivo experiments showed that circ-WHSC1 promoted NSCLC proliferation. circ-WHSC1 also promoted the migration and invasion of lung cancer cells. Through bioinformatic analysis and functional experiments, we showed that circ-WHSC1 could act as a sponge for micro-RNA-7 (miR-7) and regulate the expression of TAB2 (TGF-beta activated kinase one binding protein two). Inhibition of the circ-WHSC1/miR-7/TAB2 pathway could effectively attenuate lung cancer progression. In summary, this study confirmed the existence and oncogenic function of circ-WHSC1 in NSCLC. The research suggests that the circ-WHSC1/miR-7/TAB2 axis might be a potential target for NSCLC therapy.
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Proteínas Adaptadoras Transductoras de Señales/genética , Regulación Neoplásica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/genética , Neoplasias Pulmonares/genética , MicroARNs/genética , Oncogenes , ARN Circular/genética , Proteínas Represoras/genética , Animales , Apoptosis/genética , Carcinoma de Pulmón de Células no Pequeñas , Línea Celular Tumoral , Proliferación Celular/genética , Modelos Animales de Enfermedad , Xenoinjertos , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Ratones , Interferencia de ARN , Proteínas Represoras/metabolismoRESUMEN
OBJECTIVE: The expression levels of histone deacetylase 2 (HDAC2), eukaryotic initiation factor 5 (eIF5), and eukaryotic initiation factor 6 (eIF6), and relationship between HDAC2 and eIF5 or eIF6 in lung cancer tissues were investigated, in order to charify the relationship between HDAC2 and the prognosis of lung cancer patients and its influence on the expression of eIF5 and eIF6. METHODS: The expression of HDAC2, eIF5, and eIF6 in lung cancer tissues was detected by quantitative reverse transcription polymerase chain reaction. The expression correlation between HDAC2 and eIF5 or eIF6 was tested using a t test. The correlation between HDAC2 and eIF5 or eIF6 was analyzed using the TCGA database. The identified cells were constructed with small interfering siRNA and HDAC2 overexpression plasmid. The proliferation and migration ability of the identified cells was investigated by CCK8 and Transwell assays, respectively. RESULTS: HDAC2, eIF5, and eIF6 were overexpressed in lung cancer tissues, and HDAC2 expression level was negatively correlated with the prognosis of lung cancer patients. HDAC2 expression level was positively correlated with eIF5 and eIF6 expression levels. HDAC2 could regulate the expression of eIF5 and eIF6. The regulation of proliferation and invasion of lung cancer cells by HDAC2 depended on eIF5 and eIF6. CONCLUSION: HDAC2, eIF5, and eIF6 were closely related with lung cancer tumorigenesis, which might be potential biological markers and therapeutic targets for lung cancer.
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Carcinogénesis/genética , Factor 5 Eucariótico de Iniciación/genética , Histona Desacetilasa 2/genética , Neoplasias Pulmonares/genética , Factores de Iniciación de Péptidos/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Supervivencia sin Progresión , Interferencia de ARN , ARN Interferente Pequeño/genéticaRESUMEN
Circular RNA (circRNA) is a type of noncoding RNA that can interact with miRNAs to regulate gene expression. However, little is known concerning circRNA, which is crucial in the pathogenesis of lung cancer. To date, limited studies have explored the role of circ_0044516 in lung cancer progression. Recently, we observed that circ_0044516 expression levels were obviously elevated in lung cancer tissues and cells. A549 and SPCA1 cells were transfected with circ_0044516 siRNA. We observed that knockdown of circ_0044516 dramatically repressed cell proliferation, increased cell apoptosis, and repressed the cell cycle. Moreover, A549 and SPCA1 cell migration and invasion abilities were greatly repressed by circ_0044516 siRNA. Due to accumulating evidence demonstrating the vital role of cancer stem cells, their mechanism of involvement has drawn increasing attention in tumor progression and metastasis research. We also found that cancer stem cell properties were restrained by silencing circ_0044516 in A549 and SPC-A1 cells. Moreover, in vivo xenograft experiments showed that circ_0044516 downregulation reduced tumor growth. Mechanistically, in lung cancer and using bioinformatics, we demonstrated that circ_0044516 sponges miR-136 targeting MAT2A. Furthermore, rescue assays were carried out to identify that circ_0044516 modulates cell proliferation, invasion, and stemness by regulating miR-136 and MAT2A in lung cancer. In summary, our study revealed that the circ_0044516/miR-136/MAT2A axis is involved in lung cancer progression. Our findings may provide novel targets for diagnosis and therapeutic intervention in lung cancer patients.
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Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Metionina Adenosiltransferasa/genética , MicroARNs/metabolismo , ARN Circular/metabolismo , Células A549 , Animales , Movimiento Celular/genética , Progresión de la Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Pulmonares/patología , Invasividad Neoplásica/genética , ARN Circular/genética , Ratas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Hepatocellular carcinoma (HCC) is among the most common and lethal human cancers worldwide. Despite curative resection, high recurrence of HCC remains a big threat, leading to poor patient outcomes. Hepatitis B virus (HBV) pre-S mutants, which harbor deletions over pre-S1 and pre-S2 gene segments of large surface proteins, have been implicated in HCC recurrence. Therefore, a reliable approach for detection of pre-S mutants is urgently needed for predicting HCC recurrence to improve patient survival. In this study, we used a next-generation sequencing (NGS)-based platform for quantitative detection of pre-S mutants in the plasma of HBV-related HCC patients and evaluated their prognostic values in HCC recurrence. We demonstrated that the presence of deletions spanning the pre-S2 gene segment and the high percentage of pre-S2 plus pre-S1 + pre-S2 deletions, either alone or in combination, was significantly and independently associated with poor recurrence-free survival and had greater prognostic performance than other clinicopathological and viral factors in predicting HCC recurrence. Our data suggest that the NGS-based quantitative detection of pre-S mutants in plasma represents a promising approach for identifying patients at high risk for HBV-related HCC recurrence after surgical resection in a noninvasive manner.
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Proteínas de la Cápside/genética , Carcinoma Hepatocelular/virología , Virus de la Hepatitis B/genética , Neoplasias Hepáticas/virología , Recurrencia Local de Neoplasia/virología , Adulto , Anciano , Proteínas de la Cápside/sangre , Carcinoma Hepatocelular/sangre , Femenino , Eliminación de Gen , Genotipo , Hepatitis B Crónica/sangre , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/virología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Hepáticas/sangre , Masculino , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/sangre , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: In esophageal squamous carcinoma, lymphadenectomy along the left recurrent laryngeal nerve (RLN) is recommended owing to its highly metastatic potential. However, this procedure is difficult due to limited working space in the left upper mediastinum, and increases postoperative complications. AIM: To present a novel method for lymphadenectomy along the left RLN during thoracoscopic esophagectomy in the semi-prone position. METHODS: The fundamental concept of this novel method is to exfoliate a bilateral pedicled nerve flap, which is a two-dimensional membrane, which includes the left RLN, lymph nodes (LNs) along the left RLN, and tracheoesophageal vessels, by suspending the esophagus to the dorsal side and pushing the trachea to the ventral side (named "bilateral exposure method"). Then, the hollow-out method is performed to transform the two-dimensional membrane to a three-dimensional structure, in which the left RLN and tracheoesophageal vessels are easily distinguished and preserved during lymphadenectomy along the left RLN. This novel method was retrospectively evaluated in 116 consecutive patients with esophageal squamous carcinoma from August 2016 to February 2018. RESULTS: There were 58 patients in each group. No significant difference was found between the two groups in terms of age, gender, postoperative pneumonia, anastomotic fistula, and postoperative hospitalization. However, the number of dissected LNs along the left RLN in this novel method was significantly higher than that in the conventional method (4.17 ± 0.359 vs 2.93 ± 0.463, P = 0.0447). Moreover, the operative time and the rate of postoperative hoarseness in the novel method were significantly lower than those in the conventional method (306.0 ± 6.774 vs 335.2 ± 7.750, P = 0.0054; 4/58 vs 12/58, P = 0.0312). CONCLUSION: This novel method for lymphadenectomy along the left RLN during thoracoscopic esophagectomy in the semi-prone position is much safer and more effective.
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Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/cirugía , Esofagectomía/métodos , Escisión del Ganglio Linfático/métodos , Nervio Laríngeo Recurrente/cirugía , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Esofagectomía/efectos adversos , Femenino , Humanos , Escisión del Ganglio Linfático/efectos adversos , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Masculino , Mediastino/cirugía , Ilustración Médica , Persona de Mediana Edad , Tempo Operativo , Posicionamiento del Paciente , Complicaciones Posoperatorias/etiología , Posición Prona , Estudios Retrospectivos , Toracoscopía/efectos adversos , Toracoscopía/métodos , Resultado del TratamientoRESUMEN
Callicarpa nudiflora Vahl is a medicinal plant occurring in Guangdong, Guangxi, Hainan provinces of China. Here, we report and characterize the complete plastid genome sequence of C. nudiflora in an effort to provide genomic resources useful for promoting its conservation. The complete plastome is 154,080 bp in length and contains the typical structure and gene content of angiosperm plastome, including two inverted repeat (IR) regions of 25,657 bp, a large single-copy (LSC) region of 84,949 bp, and a small single-copy (SSC) region of 17,817 bp. There are 113 genes annotated, including 79 unique protein-coding genes, 4 unique ribosomal RNA genes, and 30 transfer RNA genes. To investigate the evolution status of C. nudiflora, as well as Verbenaceae, we constructed a phylogenetic tree with C. nudiflora and other 11 species based on their complete chloroplast genomes. According to the phylogenetic topologies, C. nudiflora was closely related to Lancea hirstua.
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Maspin is a tumor suppressor that stimulates apoptosis and inhibits metastasis in various cancer types, including hepatocellular carcinoma (HCC). Our previous study has demonstrated that HBx induced microRNA-7, 103, 107, and 21 expressions to suppress maspin expression, leading to metastasis, chemoresistance, and poor prognosis in HCC patients. However, it remains unclear how HBx elicits these microRNA expressions. HBx has been known to induce aberrant activation and nuclear translocation of inhibitor-κB kinase-α (IKKα) to promote HCC progression. In this study, our data further revealed that nuclear IKKα expression was inversely correlated with maspin expression in HBV-associated patients. Nuclear IKKα but not IKKß reduced maspin protein and mRNA expression, and inhibition of IKKα reverses HBx-mediated maspin downregulation and chemoresistance. In response to HBx overexpression, nuclear IKKα was further demonstrated to induce the gene expressions of microRNA-7, -103, -107, and -21 by directly targeting their promoters, thereby leading to maspin downregulation. These findings indicated nuclear IKKα as a critical regulator for HBx-mediated microRNA induction and maspin suppression, and suggest IKKα as a promising target to improve the therapeutic outcome of HCC patients.
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Carcinoma Hepatocelular/genética , Regulación Neoplásica de la Expresión Génica , Virus de la Hepatitis B/fisiología , Quinasa I-kappa B/metabolismo , Neoplasias Hepáticas/genética , MicroARNs/metabolismo , Serpinas/metabolismo , Transactivadores/genética , Apoptosis , Biomarcadores de Tumor/metabolismo , Carcinogénesis/genética , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Línea Celular Tumoral , Núcleo Celular/metabolismo , Progresión de la Enfermedad , Regulación hacia Abajo , Resistencia a Antineoplásicos/genética , Genes Supresores de Tumor , Células HEK293 , Histonas/metabolismo , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Fosforilación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Serpinas/genética , Transducción de Señal , Transactivadores/metabolismo , Proteínas Reguladoras y Accesorias ViralesRESUMEN
Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) inhibitors decreasing serum cholesterol and have shown promise in cancer prevention. In this study, we demonstrated the oncogenic role of HMGR in colorectal cancer (CRC) by disclosing increased HMGR activity in CRC patients and its enhancement of anti-apoptosis and stemness. Our previous studies showed that statins containing carboxylic acid chains possessed activity against histone deacetylases (HDACs), and strengthened their anti-HDAC activity through designing HMGR-HDAC dual inhibitors, JMF compounds. These compounds exerted anti-cancer effect in CRC cells as well as in AOM-DSS and Apc(Min/+) CRC mouse models. JMF mostly regulated the genes related to apoptosis and inflammation through genome-wide ChIP-on-chip analysis, and Ingenuity Pathways Analysis (IPA) predicted their respective regulation by NR3C1 and NF-κB. Furthermore, JMF inhibited metastasis, angiogenesis and cancer stemness, and potentiated the effect of oxaliplatin in CRC mouse models. Dual HMGR-HDAC inhibitor could be a potential treatment for CRC.
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Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/metabolismo , Hidroximetilglutaril-CoA Reductasas/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Terapia Molecular Dirigida , Animales , Antineoplásicos/farmacología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Estudio de Asociación del Genoma Completo , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Masculino , Ratones , Ratones Transgénicos , Metástasis de la Neoplasia , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Poor prognosis of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) involves HBV X protein (HBx)-induced tumor progression. HBx also contributes to chemo-resistance via inducing the expressions of anti-apoptosis and multiple drug resistance genes. However, the impact of HBx expression on the therapeutic efficacy of various receptor tyrosine kinase inhibitors remains unknown. In this study, our data showed that HBx overexpression did not alter the cellular sensitivity of HCC cell lines to sorafenib but unexpectedly enhanced the cell death induced by EGFR family inhibitors, including gefitinib, erlotinib, and lapatinib due to ErbB3 up-regulation. Mechanistically, HBx transcriptionally up-regulates ErbB3 expression in a NF-κB dependent manner. In addition, HBx also physically interacts with ErbB2 and ErbB3 proteins and enhances the formation of ErbB2/ErbB3 heterodimeric complex. The cell viability of HBx-overexpressing cells was decreased by silencing ErbB3 expression, further revealing the pivotal role of ErbB3 in HBx-mediated cell survival. Our data suggest that HBx shifts the oncogenic addiction of HCC cells to ErbB2/ErbB3 signaling pathway via inducing ErbB3 expression and thereby enhances their sensitivity to EGFR/ErbB2 inhibitors.
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Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Quinazolinas/farmacología , Receptor ErbB-3/metabolismo , Transactivadores/metabolismo , Apoptosis/efectos de los fármacos , Apoptosis/genética , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/metabolismo , Virus de la Hepatitis B/fisiología , Humanos , Lapatinib , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virología , FN-kappa B/genética , FN-kappa B/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Interferencia de ARN , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-3/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transactivadores/genética , Regulación hacia Arriba/efectos de los fármacos , Proteínas Reguladoras y Accesorias ViralesRESUMEN
Maspin suppresses tumor progression by promoting cell adhesion and apoptosis and by inhibiting cell motility. However, its role in tumorigenesis of hepatocellular carcinoma (HCC) remains unclear. The gene regulation of maspin and its relationship with HCC patient prognosis were investigated in this study. Maspin expression was specifically reduced in HBV-associated patients and correlated with their poor prognosis. Maspin downregulation in HCC cells was induced by HBx to promote their motility and resistance to anoikis and chemotherapy. HBx-dependent induction of microRNA-7, -107, and -21 was further demonstrated to directly target maspin mRNA, leading to its protein downregulation. Higher expressions of these microRNAs also correlated with maspin downregulation in HBV-associated patients, and were associated with their poor overall survival. These data not only provided new insights into the molecular mechanisms of maspin deficiency by HBx, but also indicated that downregulation of maspin by microRNAs confers HBx-mediated aggressiveness and chemoresistance in HCC.
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Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroARNs/genética , Serpinas/genética , Transactivadores/genética , Regiones no Traducidas 3'/genética , Anoicis/efectos de los fármacos , Anoicis/genética , Antineoplásicos/farmacología , Western Blotting , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/virología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Células Hep G2 , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/metabolismo , Virus de la Hepatitis B/fisiología , Interacciones Huésped-Patógeno/genética , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/virología , Masculino , Análisis Multivariante , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Serpinas/metabolismo , Transactivadores/metabolismo , Proteínas Reguladoras y Accesorias ViralesRESUMEN
Lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, has been shown to improve the survival rate of patients with advanced HER2-positive breast cancers. However, the off-target activity of lapatinib in inducing EGFR expression without tyrosine kinase activity was demonstrated to render HER2-negative breast cancer cells more metastatic, suggesting a limitation to the therapeutic effectiveness of this dual inhibitor in HER2-heterogeneous tumors. Therefore, targeting EGFR expression may be a feasible approach to improve the anticancer efficiency of lapatinib-based therapy. Inhibition of HDAC has been previously reported to epigenetically suppress EGFR protein expression. In this study, however, our data indicated that treatment with HDAC inhibitors trichostatin A (TSA), but not suberoylanilide hydroxamic acid (SAHA) or HDAC siRNA, can attenuate both protein and mRNA expressions of EGFR in lapatinib-treated triple-negative breast cancer cells, suggesting that TSA may suppress EGFR expression independently of HDAC inhibition. Nevertheless, TSA reduced EGFR 3'UTR activity and induced the gene expression of microRNA-7, a known EGFR-targeting microRNA. Furthermore, treatment with microRNA-7 inhibitor attenuated TSA-mediated EGFR suppression. These results suggest that TSA induced microRNA-7 expression to downregulate EGFR expression in an HDAC-independent manner.
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Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histona Desacetilasas/genética , Ácidos Hidroxámicos/farmacología , MicroARNs/genética , Quinazolinas/farmacología , Antineoplásicos/farmacología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Lapatinib , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genéticaRESUMEN
Hepatitis B virus- (HBV-) associated hepatocellular carcinoma (HCC) is the most common type of liver cancer. However, the underlying mechanism of HCC tumorigenesis is very complicated and HBV-encoded X protein (HBx) has been reported to play the most important role in this process. Activation of downstream signal pathways of epidermal growth factor receptor (EGFR) family is known to mediate HBx-dependent HCC tumor progression. Interestingly, HER2 (also known as ErbB2/Neu/EGFR2) is frequently overexpressed in HBx-expressing HCC patients and is associated with their poor prognosis. However, it remains unclear whether and how HBx regulates HER2 expression. In this study, our data showed that HBx expression increased HER2 protein level via enhancing its mRNA stability. The induction of RNA-binding protein HuR expression by HBx mediated the HER2 mRNA stabilization. Finally, the upregulated HER2 expression promoted the migration ability of HBx-expressing HCC cells. These findings deciphered the molecular mechanism of HBx-mediated HER2 upregulation in HBV-associated HCC.
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Proteínas ELAV/metabolismo , Regulación Neoplásica de la Expresión Génica , Virus de la Hepatitis B/metabolismo , Neoplasias Hepáticas/metabolismo , Receptor ErbB-2/biosíntesis , Transactivadores/metabolismo , Células Hep G2 , Virus de la Hepatitis B/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Estabilidad del ARN/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Receptor ErbB-2/genética , Transactivadores/genética , Regulación hacia Arriba/genética , Proteínas Reguladoras y Accesorias ViralesRESUMEN
BACKGROUND: Granular cell tumors (GCT), especially in the esophagus, are rare neoplasms originating from the nervous system. There is still some controversy regarding the diagnosis and treatment of esophageal GCT. METHODS: We report 14 cases of esophageal GCT diagnosed and treated from January 2004 to March 2013. Their clinical manifestations, endoscopic image, endoscopic ultrasonography (EUS) appearance, pathology, immunohistochemistry, treatment, and prognosis were reviewed. RESULTS: The typical images of EUS were hypoechoic, homogenous, and smooth-edged tumors restricted to deep mucosal and submucosal layers. However, there were 2 cases with tumors invading muscular layer. Endoscopic ultrasonography was valuable to assess the tumor size, location, depth of invasion, and nature. According to EUS manifestation, 11 cases with lesions 3 cm or less in diameter without muscular layer invasion underwent endoscopic resection without complication and the other 3 cases underwent surgical resection. A new technique of submucosal tunnel endoscopic resection was performed in 3 submucosal cases with lesions ranging from 2 cm to 3 cm in diameter. All of these cases were benign and histology was necessary for differential diagnosis. CONCLUSIONS: Endoscopic ultrasonography plays an important guiding role in the diagnosis and treatment of esophageal GCT. Submucosal tunnel endoscopic resection is safe and effective. Further study is needed to determine whether this technique can be expanded into other applications.
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Endosonografía/métodos , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/cirugía , Tumor de Células Granulares/diagnóstico por imagen , Tumor de Células Granulares/cirugía , Adulto , Biopsia con Aguja , Supervivencia sin Enfermedad , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Esofagectomía/métodos , Esofagoscopía/métodos , Femenino , Estudios de Seguimiento , Tumor de Células Granulares/mortalidad , Tumor de Células Granulares/patología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Medición de Riesgo , Muestreo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
INTRODUCTION: Triple-negative breast cancer (TNBC), a subtype of breast cancer with negative expressions of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is frequently diagnosed in younger women and has poor prognosis for disease-free and overall survival. Due to the lack of known oncogenic drivers for TNBC proliferation, clinical benefit from currently available targeted therapies is limited, and new therapeutic strategies are urgently needed. METHODS: Triple-negative breast cancer cell lines were treated with proteasome inhibitors in combination with lapatinib (a dual epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor). Their in vitro and in vivo viability was examined by MTT assay, clonogenic analysis, and orthotopic xenograft mice model. Luciferase reporter gene, immunoblot, and RT-qPCR, immunoprecipitation assays were used to investigate the molecular mechanisms of action. RESULTS: Our data showed that nuclear factor (NF)-κB activation was elicited by lapatinib, independent of EGFR/HER2 inhibition, in TNBCs. Lapatinib-induced constitutive activation of NF-κB involved Src family kinase (SFK)-dependent p65 and IκBα phosphorylations, and rendered these cells more vulnerable to NF-κB inhibition by p65 small hairpin RNA. Lapatinib but not other EGFR inhibitors synergized the anti-tumor activity of proteasome inhibitors both in vitro and in vivo. Our results suggest that treatment of TNBCs with lapatinib may enhance their oncogene addiction to NF-κB, and thus augment the anti-tumor activity of proteasome inhibitors. CONCLUSIONS: These findings suggest that combination therapy of a proteasome inhibitor with lapatinib may benefit TNBC patients.