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Exosomes represent a type of extracellular vesicles derived from the endosomal pathway that transport diverse molecular cargoes such as proteins, lipids, and nucleic acids. These cargoes have emerged as crucial elements impacting disease diagnosis, treatment, and prognosis, and are integral to the process of exosome formation. This review delves into the essential molecular cargoes implicated in the phases of exosome production and release. Emphasis is placed on their significance as cancer biomarkers and potential therapeutic targets, accompanied by an exploration of the obstacles and feasible applications linked to these developments.
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Exosomas , Neoplasias , Exosomas/metabolismo , Humanos , Neoplasias/diagnóstico , Neoplasias/metabolismo , Animales , Biomarcadores de Tumor/metabolismoRESUMEN
BACKGROUND: Neuroendocrine prostate cancer (NEPC), a lethal subset of prostate cancer (PCa), is characterized by loss of AR signaling and resistance to AR-targeted therapy. While it is well reported that second-generation AR blockers induce neuroendocrine (NE) trans-differentiation of castration-resistant prostate cancer (CRPC) to promote the occurrence of NEPC, and pluripotent transcription factors might be potential regulators, the underlying molecular mechanisms remain unclear. METHODS: We analyzed the data from public databsets to screen candidate genes and then focused on SOX4, a regulator of NE trans-differentiation. The expression changes of SOX4 and its relationship with tumor progression were validated in clinical tumor tissues. We evaluated malignant characteristics related to NEPC in prostate cancer cell lines with stable overexpression or knockdown of SOX4 in vitro. Tumor xenografts were analyzed after inoculating the relevant cell lines into nude mice. RNA-seq, ATAC-seq, non-targeted metabolomics analysis, as well as molecular and biochemical assays were carried out to determine the mechanism. RESULTS: We screened public datasets and identified that expression of SOX4 was significantly elevated in NEPC. Overexpressing SOX4 in C4-2B cells increased cell proliferation and migration, upregulated the expression of NE marker genes, and inhibited AR expression. Consistently, inhibition of SOX4 expression in DU-145 and PC-3 cells reduced the above malignant phenotypes and repressed the expression of NE marker genes. For the in vivo assay, we found that knockdown of SOX4 inhibited tumor growth of subcutaneous xenografts in castrated nude mice which were concomitantly treated with enzalutamide (ENZ). Mechanically, we identified that one of the key enzymes in gluconeogenesis, PCK2, was a novel target of SOX4. The activation of carbohydrate metabolism reprogramming by SOX4 could promote NE trans-differentiation via the SOX4/PCK2 pathway. CONCLUSIONS: Our findings reveal that SOX4 promotes NE trans-differentiation both in vitro and in vivo via directly enhancing PCK2 activity to activate carbohydrate metabolism reprogramming. The SOX4/PCK2 pathway and its downstream changes might be novel targets for blocking NE trans-differentiation.
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Transdiferenciación Celular , Neoplasias de la Próstata Resistentes a la Castración , Factores de Transcripción SOXC , Transducción de Señal , Animales , Humanos , Masculino , Ratones , Línea Celular Tumoral , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/metabolismo , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/genética , Ratones Desnudos , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Factores de Transcripción SOXC/genética , Factores de Transcripción SOXC/metabolismoRESUMEN
MHY1485 is an mTOR activator that inhibits the autophagy process by inhibiting the fusion between autophagosomes and lysosomes. This study aimed to explore the role and mechanism of MHY1485 in hepatocellular carcinoma (HCC) and to provide an in-depth understanding of the mechanisms of autophagy regulation in relation to adriamycin (ADM) resistance, as well as the development of a molecularly targeted autophagy-modulating approach. Here, ADM was used to treat HepG2 cells and construct an ADM-resistant cell model. The HepG2/ADM cell line and HepG2 cells were treated with MHY1485 and ADM, respectively, and the proliferation and apoptosis of HCC cells were detected using CCK8, clone formation, flow cytometry, and 5-ethynyl-2'-deoxyuridine staining assays. Ki-67, mTOR phosphorylation, and LC3A expression were detected by IF staining; the expression or phosphorylation levels of autophagy-related proteins (i.e., GLUT1, PGI, PFK, END, and MTHFD2) and apoptosis-related proteins (caspase-3, caspase-8, and caspase-9) were detected by qPCR and western blotting. The number of autophagosomes was determined by monodansylcadaverine staining. Our results showed that MHY1485 can inhibit the proliferation and growth of liver cancer cells, and that MHY1485 combined with ADM can effectively inhibit the tolerance of HepG2/ADM cells to ADM and enhance the efficacy of ADM. The results of the detection of the autophagy-related protein LC3A also indicated that MHY1485 activates mTOR and can affect the phosphorylation level of ULK1, inhibit autophagy, and enhance the sensitivity of liver cancer cells to adriamycin. In summary, MHY1485 can enhance the sensitivity of adriamycin-resistant cells to adriamycin by activating mTOR and blocking the autophagy process in cells; therefore, mTOR may become a potential target for the treatment of liver cancer.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Morfolinas , Triazinas , Humanos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Doxorrubicina/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Células Hep G2 , Apoptosis , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Autofagia , Proliferación Celular , Línea Celular TumoralRESUMEN
BACKGROUND: Hypereosinophilic syndrome (HES) is classified as primary, secondary or idiopathic. Idiopathic HES (IHES) has a variable clinical presentation and may involve multiple organs causing severe damage. Hepatic sinusoidal obstruction syndrome (HSOS) is characterized by damage to the endothelial cells of the hepatic sinusoids of the hepatic venules, with occlusion of the hepatic venules, and hepatocyte necrosis. We report a case of IHES with HSOS of uncertain etiology. CASE SUMMARY: A 70-year-old male patient was admitted to our hospital with pruritus and a rash on the extremities for > 5 mo. He had previously undergone antiallergic treatment and herbal therapy in the local hospital, but the symptoms recurred. Relevant examinations were completed after admission. Bone marrow aspiration biopsy showed a significantly higher percentage of eosinophils (23%) with approximately normal morphology. Ultrasound-guided hepatic aspiration biopsy indicated HSOS. Contrast-enhanced computed tomography (CT) of the upper abdomen showed hepatic venule congestion with hydrothorax and ascites. The patient was initially diagnosed with IHES and hepatic venule occlusion. Prednisone, low molecular weight heparin and ursodeoxycholic acid were given for treatment, followed by discontinuation of low molecular weight heparin due to ecchymosis. Routine blood tests, biochemical tests, and imaging such as enhanced CT of the upper abdomen and pelvis were reviewed regularly. CONCLUSION: Hypereosinophilia may play a facilitating role in the occurrence and development of HSOS.
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Under aerobic conditions, the preferential use of anaerobic glycolysis by tumour cells leads to a high level of lactate accumulation in tumour microenvironment. Lactate acts not only as a cellular energy source but also as a signalling molecule that regulates cancer cell growth, metastasis and metabolism. It has been reported that a Gproteincoupled receptor for lactate named hydroxycarboxylic acid receptor 1 (HCAR1) is highly expressed in numerous types of cancer, but the detailed mechanism remains unclear. In the present study, it was reported that HCAR1 is highly expressed in breast cancer cells. Genetic deletion of HCAR1 in MCF7 cells leads to reduced cell proliferation and migration. Moreover, it was observed that knockout (KO) of HCAR1 attenuated the expression and activity of phosphofructokinase and hexokinase, key ratelimiting enzymes in glycolysis. Using an extracellular flux analyzer, it was showed that KO of HCAR1 promoted a metabolic shift towards a decreased glycolysis state, as evidenced by a decreased extracellular acidification rate and increased oxygen consumption rate in MCF7 cells. Taken together, our results suggested that lactate acts through HCAR1 as a metabolic regulator in breast cancer cells that may be therapeutically exploited.
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Neoplasias de la Mama , Receptores Acoplados a Proteínas G , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Metabolismo Energético , Femenino , Glucólisis , Humanos , Ácido Láctico/metabolismo , Células MCF-7 , Metástasis de la Neoplasia , Receptores Acoplados a Proteínas G/metabolismo , Microambiente TumoralRESUMEN
Inflammasome contributes to the pathogenesis of various inflammatory diseases, but the epigenetic mechanism controlling its activation remains elusive. Here, we found that the histone methyltransferase Ezh2 mediates the activation of multiple types of inflammasomes in macrophages/microglia independent of its methyltransferase activity and thus promotes inflammasome-related pathologies. Mechanistically, Ezh2 functions through its SANT2 domain to maintain the enrichment of H3K27 acetylation in the promoter region of the long noncoding RNA (lncRNA) Neat1, thereby promoting chromatin accessibility and facilitating p65-mediated transcription of Neat1, which is a critical mediator of inflammasome assembly and activation. In addition, the tumour suppressor protein p53 competes with Ezh2 for the same binding region in the Neat1 promoter and thus antagonises Ezh2-induced Neat1 transcription and inflammasome activation. Therefore, loss of Ezh2 strongly promotes the binding of p53, which recruits the deacetylase SIRT1 for H3K27 deacetylation of the Neat1 promoter and thus suppresses Neat1 transcription and inflammasome activation. Overall, our study demonstrates an epigenetic mechanism involved in modulating inflammasome activation through an Ezh2/p53 competition model and highlights a novel function of Ezh2 in maintaining H3K27 acetylation to support lncRNA Neat1 transcription.
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ARN Largo no Codificante , Cromatina , Histona Metiltransferasas/genética , Histona Metiltransferasas/metabolismo , Inflamasomas/metabolismo , ARN Largo no Codificante/metabolismo , Sirtuina 1/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Background: Over the past 40 years, endoscopic ultrasound (EUS) has become a safe and effective tool for both diagnostic and therapeutic applications. A growing number of articles have been published annually. We aimed to explore global scientific outputs and hotspots of EUS published by different countries, organizations, and authors. Methods: The global literature regarding EUS during the 1900-2020 period was identified from the Web of Science (WOS) Core database. "Bibliometrix" and software VOSviewer were applied to perform bibliometric analysis. Results: The annual growth rate of publications from 1980 to 2020 was around 16% and the number of EUS-related articles had experienced a sudden increase in the last decade. Bhutani MS was the most productive author over the past years, with 94 publications. Hawes RH had the highest number of citations, with 6,034 citations. The United States and institutions from United States dominated the EUS research. Among the journals, GASTROINTESTINAL ENDOSCOPY published the highest number of articles, followed by ENDOSCOPY. The majority of top 10 frequently cited references were cited more than 200 times. Carcinoma, diagnosis, fine-needle-aspiration, cytology, and pancreatitis were the important keywords in co-occurrence analysis of keywords. Recent studies focused more on tissue acquisition, size of the needle, lumen-apposing metal stent, and fine-needle- biopsy. Conclusion: Research on EUS has significantly increased in the last decade globally and it will continue to increase. Active collaboration among different authors and countries was observed in the EUS field. Tissue acquisition, size of the needle, apposing metal stent, and fine-needle-biopsy might be the latest research frontiers and should receive more attention.
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BACKGROUND: Primary peritoneal serous carcinoma (PPSC) is a rare tumor that lacks a prognostic prediction model. Our study aims to develop a nomogram to predict overall survival (OS) of PPSC patients. METHODS: Patients confirmed to have PPSC between 2004 and 2012 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. LASSO and multivariate Cox regression analyses were used to screen for meaningful independent prognostic factors to construct a nomogram model for 3-, 5-, and 10-year OS among patients with PPSC. The nomogram compared the discrimination, calibration, and net benefits with the International Federation of Gynecology and Obstetrics (FIGO) staging system of PPSC patients. RESULTS: Eight variables were selected to establish the nomogram for PPSC. The established nomogram performed significantly better than the FIGO staging system (p < 0.05). The 3-, 5-, and 10-year OS of PPSC was 0.498, 0.306, and 0.152, respectively. Patients of old age, widowed marital status, grade high, FIGO IIIB, IIIC, or IV, lymph node metastasis, no lymphadenectomy, no surgery, and no chemotherapy got higher score which corresponds with higher risk and lower OS. In the multivariate Cox regression analysis, age, histological grade, FIGO staging, lymph node metastasis, and lymphadenectomy (four or more) were identified as independent prognostic factors for PPSC. CONCLUSIONS: PPSC patients have distinct characteristics with respect to their presentation and survival outcomes. A prognostic nomogram constructed by various clinical indicators can provide better and more accurate predictions for patients with PPSC.
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Gastric cancer (GC) is the third leading cause of cancerrelated mortality and the fifth most common type of cancer worldwide. GC stem cells (GCSCs) have been reported to be responsible for the malignant behavior of GC. However, the key molecular mechanism controlling GCSC function remains unclear. The present study aimed to investigate the function of retinoic acidrelated orphan receptor ß (RORß) in GC. The expression levels of RORß in GC cells and clinical GC tissues were analyzed using western blotting, reverse transcriptionquantitative PCR (RTqPCR) and immunohistochemistry. The association between RORß expression levels and GCSC markers was analyzed using Gene Set Enrichment Analysis, and GeneChip was performed to identify differentially expressed genes between control and RORßoverexpressing GC cells. CCK8 and flow cytometric assays were used to evaluate the effect of RORß on cell viability and apoptosis, respectively. The effect of RORß on the selfrenewal capacity of GCSCs was measured using a sphere formation assay, the expression levels of induced pluripotent stem (iPS) factors and epithelialmesenchymal transition (EMT)related factors were measured by RTqPCR and western blotting, and the tumorigenic capacity was measured by an in vivo mouse model. Finally, the impact of RORß on the Wnt signaling pathway was determined using western blotting and a TOP/FOP flash assay. The results revealed that the expression levels of RORß were downregulated in GC tissues compared with paracarcinoma tissues, and were inversely associated with the expression levels of GCSC markers. The overexpression of RORß upregulated the expression levels of the proapoptotic gene, Bcl2 like protein 11, which subsequently inhibited the viability and promoted the apoptosis of GC cells. In addition, RORß decreased the sphere forming ability, and downregulated the expression levels of iPS cell and EMTrelated factors. In vivo, RORß suppressed the tumorigenic capacity and stemness of GC cells. Mechanistically, RORß was revealed to decrease the activity of the Wnt/ßcatenin signaling pathway in GCSCs. In conclusion, the findings of the present study identified RORß as a novel suppressor of GCSCs and highlighted the prospect of RORß as a novel candidate target for stem cellbased GC therapy.
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Regulación hacia Abajo , Células Madre Neoplásicas/metabolismo , Miembro 2 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 2 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Neoplasias Gástricas/patología , Adulto , Anciano , Animales , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Transición Epitelial-Mesenquimal , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Persona de Mediana Edad , Trasplante de Neoplasias , Células Madre Neoplásicas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Análisis de Supervivencia , Vía de Señalización WntRESUMEN
TGFß is essential for the generation of anti-tumor Th9 cells; on the other hand, it causes resistance against anti-tumor immunity. Despite recent progress, the underlying mechanism reconciling the double-edged effect of TGFß signaling in Th9-mediated cancer immunotherapy remains elusive. Here, we find that TGFß-induced down-regulation of bifunctional apoptosis regulator (BFAR) represents the key mechanism preventing the sustained activation of TGFß signaling and thus impairing Th9 inducibility. Mechanistically, BFAR mediates K63-linked ubiquitination of TGFßR1 at K268, which is critical to activate TGFß signaling. Thus, BFAR deficiency or K268R knock-in mutation suppresses TGFßR1 ubiquitination and Th9 differentiation, thereby inhibiting Th9-mediated cancer immunotherapy. More interestingly, BFAR-overexpressed Th9 cells exhibit promising therapeutic efficacy to curtail tumor growth and metastasis and promote the sensitivity of anti-PD-1-mediated checkpoint immunotherapy. Thus, our findings establish BFAR as a key TGFß-regulated gene to fine-tune TGFß signaling that causes Th9 induction insensitivity, and they highlight the translational potential of BFAR in promoting Th9-mediated cancer immunotherapy.
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Proteínas Adaptadoras Transductoras de Señales/inmunología , Proteínas Reguladoras de la Apoptosis/inmunología , Proteínas de la Membrana/inmunología , Neoplasias/inmunología , Neoplasias/terapia , Transducción de Señal/inmunología , Factor de Crecimiento Transformador beta/inmunología , Animales , Diferenciación Celular/inmunología , Regulación hacia Abajo/inmunología , Humanos , Inmunoterapia/métodos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
BACKGROUND: Anti-tumour necrosis factor (anti-TNF) therapy increases the risk of tuberculosis (TB). Given limitations of screening techniques, it remains uncertain if patients receiving anti-TNF in TB endemic regions should be screened for latent infection with chemoprophylaxis restricted to those with proven infection, or if all patients should receive chemoprophylaxis. AIMS: To compare the incidence of active TB with infliximab (IFX) following targeted and universal TB chemoprophylaxis, and to determine the rates of adverse events (AE) related to TB chemoprophylaxis METHODS: A multi-centre retrospective cohort study was performed at 18 hospitals in China of 1968 adult patients with IBD receiving IFX from 2009 to 2017. TB screening prior to IFX was performed with chest X-ray and/or computed tomography [CT] and immune reactivity testing (interferon-γ release assay and/or tuberculin skin test). Patients were followed-up for a minimum of 3 months after IFX discontinuation, or until last hospital visit if IFX therapy was ongoing. Targeted strategy was defined as TB chemoprophylaxis only for patients with a positive latent TB screen, with universal strategy defined as TB chemoprophylaxis for all patients. RESULTS: Mean follow-up was 1.07 ± 0.87 years with a total follow-up of 2102 patient-years. There were 1433 patients in the targeted and 483 patients in the universal TB chemoprophylaxis groups, with no significant difference in the incidence rates of active TB between groups (673.3 per 100 000 population per year vs 891.5 per 100 000 population per year, P = 0.60). In the targeted group, 55/1433 patients received TB chemoprophylaxis compared with 483/483 in the universal group, with significantly fewer AEs related to TB chemoprophylaxis in the targeted compared to the universal group (0.35% (5/1433) vs 6.8% (33/483), P < 0.05). CONCLUSIONS: In this study of patients receiving IFX in a TB endemic area, universal chemoprophylaxis was not associated with a reduced risk of active TB when compared to a targeted chemoprophylaxis strategy, and AEs were more common. This supports the use of targeted TB chemoprophylaxis when anti-TNF therapy is initiated in TB endemic regions.
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Enfermedades Inflamatorias del Intestino , Tuberculosis Latente , Tuberculosis , Adulto , Quimioprevención , China , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/epidemiología , Tuberculosis Latente/prevención & control , Estudios Retrospectivos , Prueba de Tuberculina , Tuberculosis/epidemiología , Tuberculosis/prevención & control , Factor de Necrosis Tumoral alfa/uso terapéuticoRESUMEN
PURPOSE: Case reports suggest that ruxolitinib-containing treatment could increase the clinical response rate of patients with hemophagocytic syndrome (HPS). This study aimed to explore the effect of ruxolitinib-containing treatment for patients with lymphoma-associated hemophagocytic syndrome (LAHS). METHODS: This was a retrospective study of patients with LAHS hospitalized at the First Affiliated Hospital of Guangdong Pharmaceutical University between October 2017 and September 2019. Patients were treated with HLH-94 (etoposide and dexamethasone) or R-DED regimen (ruxolitinib, doxorubicin, etoposide, and dexamethasone). The clinical characteristics, treatment responses, and overall survival (OS) were compared. The patients were divided into the HLH-94 group (n = 34) and the R-DED group (n = 36). RESULTS: Compared with HLH-94, R-DED might effectively improve the clinical manifestations, including fever and splenomegaly in patients with LAHS, and control the systemic cytokine storm. The response rate at 2 weeks was 54.8% in the HLH-94 group, which was lower than in the R-DED group (83.3%) (p = 0.011). The OS was significantly prolonged in the R-DED group compared with the HLH-94 group (median, 5 vs. 1.5 months, p = 0.003). The multivariable analysis showed that lower IL-10 levels [hazard ratio (HR)] = 1.000, [95% confidence interval (CI)] 1.000-1.000, p = 0.012), R-DED regimen (HR = 0.196, 95% CI 0.084-0.457, p < 0.001), and non-NK/T-cell lymphoma (HR = 0.254, 95% CI 0.102-0.628, p = 0.003) were associated with better OS. The prognosis of patients with LAHS was generally poor. CONCLUSION: Ruxolitinib can be combined with chemotherapy in HPS. It is feasible, with no early signals of increased toxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfohistiocitosis Hemofagocítica/etiología , Linfoma/complicaciones , Linfoma/tratamiento farmacológico , Adulto , Dexametasona/administración & dosificación , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Pirazoles/administración & dosificación , Pirimidinas , Estudios RetrospectivosRESUMEN
Tumor protein p53-inducible nuclear protein 1 (TP53INP1) is a tumor suppressor associated with malignant tumor metastasis. In addition, it has been reported that hsa-microRNA (miR)-3934 serves key roles in various types of lung cancer, including small-cell lung carcinomas (SCLC) and non-SCLC (NSCLC). Therefore, the present study aimed to determine the effects of miR-3934-5p on cell proliferation and apoptosis, and on sensitivity to cisplatin (DDP). Reverse transcription-quantitative polymerase chain reaction analysis and western blotting were conducted for the analysis of mRNA and protein expression, respectively. Furthermore, the target of miR-3934-5p was investigated using a luciferase reporter assay and apoptosis was analyzed by flow cytometry. The results demonstrated that miR-3934-5p was upregulated in NSCLC tissues and A549 cells. Increases in the half-maximal inhibitory concentration (IC50) and the expression of miR-3934-5p were observed in the A549/DDP group. miR-3934-5p mimic promoted the expression of miR-3934-5p and the IC50 of the A549 cells. miR-3934-5p inhibitor downregulated miR-3934-5p and reduced the IC50 of A549/DDP cells. miR-3934-5p was revealed to target the 3'-untranslated region of TP53INP1. The downregulation of miR-3934-5p significantly suppressed the proliferation and promoted the apoptosis of A549/DDP cells, which were reversed by transfection with TP53INP1 small interfering (si)RNA. The protein and mRNA expression levels of TP53INP1, B-cell lymphoma 2 (Bcl-2)-associated-X and p21 were significantly increased, whereas those of Bcl-2 were significantly decreased in the miR-3934-5p inhibitor group, which was significantly reduced by TP53INP1 siRNA transfection. miR-3934-5p, as a tumor suppressor in NSCLC, may promote the sensitivity of cells to DDP by targeting TP53INP1, associated with the suppression of cell proliferation and promotion of apoptosis.
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Vernalization is required for floral initiation in Dendrobium. Interestingly, those beneficial effects can also be achieved by exogenous cytokinin application in greenhouses. Thus, an as yet unknown crosstalk/interaction may exist between vernalization and cytokinin signaling pathways. In this study, we showed, by de novo transcriptome assembly using RNA-seq data from both vegetative and reproductive tissue samples, that some floral transition-related genes-DnVRN1, FT, SOC1, LFY and AP1-were differentially expressed in low-temperature-challenged (LT) or thidiazuron (TDZ)-treated plants, compared to those mock-treated (CK). Both LT and TDZ upregulated SOC1, LFY and AP1, while the upregulation of DnVRN1 and FT was only LT-induced. We further found that LT promoted the upregulation of some key cytokinin signaling regulators, including several cytokinin biosynthesis-related genes and type-B response regulator (RR)-encoding genes, and that both LT and TDZ triggered the significant upregulation of some marker genes in the gibberellin (GA) signaling pathway, indicating an important low temperature-cytokinin-GA axis in flowering. Our data thus have revealed a cytokinin-GA signal network underlying vernalization, providing a novel insight into further investigation of the molecular mechanism of floral initiation in Dendrobium.
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Citocinas/metabolismo , Dendrobium/crecimiento & desarrollo , Flores/crecimiento & desarrollo , Transcriptoma , Frío , Dendrobium/efectos de los fármacos , Flores/efectos de los fármacos , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Filogenia , Proteínas de Plantas/metabolismoRESUMEN
BACKGROUND: Colorectal cancer remains one of the most common malignant tumors worldwide. Colorectal cancer initiating cells (CCICs) are a small subpopulation responsible for malignant behaviors of colorectal cancer. Aberrant activation of the Wnt pathways regulates the self-renewal of CCIC. However, the underlying mechanism(s) remain poorly understood. METHODS: Via retroviral library screening, we identified Nuclear Receptor-Interacting Protein 2 (NRIP2) as a novel interactor of the Wnt pathway from enriched colorectal cancer colosphere cells. The expression levels of NRIP2 and retinoic acid-related orphan receptor ß (RORß) were further examined by FISH, qRT-PCR, IHC and Western blot. NRIP2 overexpressed and knockdown colorectal cancer cells were produced to study the role of NRIP2 in Wnt pathway. We also verified the binding between NRIP2 and RORß and investigated the effect of RORß on CCICs both in vitro and in vivo. Genechip-scanning speculated downstream target HBP1. Western blot, ChIP and luciferase reporter were carried to investigate the interaction between NRIP2, RORß, and HBP1. RESULTS: NRIP2 was significantly up-regulated in CCICs from both cell lines and primary colorectal cancer tissues. Reinforced expression of NRIP2 increased Wnt activity, while silencing of NRIP2 attenuated Wnt activity. The transcription factor RORß was a key target through which NRIP2 regulated Wnt pathway activity. RORß was a transcriptional enhancer of inhibitor HBP1 of the Wnt pathway. NRIP2 prevented RORß to bind with downstream HBP1 promoter regions and reduced the transcription of HBP1. This, in turn, attenuated the HBP1-dependent inhibition of TCF4-mediated transcription. CONCLUSIONS: NRIP2 is a novel interactor of the Wnt pathway in colorectal cancer initiating cells. interactions between NRIP2, RORß, and HBP1 mediate a new mechanism for CCIC self-renewal via the Wnt activity.
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Neoplasias Colorrectales/metabolismo , Proteínas de Unión al ADN/genética , Proteínas del Grupo de Alta Movilidad/genética , Células Madre Neoplásicas/metabolismo , Proteínas del Tejido Nervioso/genética , Miembro 2 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Proteínas Represoras/genética , Regulación hacia Arriba , Animales , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Proteínas de Unión al ADN/metabolismo , Regulación Neoplásica de la Expresión Génica , Células HT29 , Proteínas del Grupo de Alta Movilidad/metabolismo , Humanos , Ratones , Trasplante de Neoplasias , Proteínas del Tejido Nervioso/metabolismo , Miembro 2 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Regiones Promotoras Genéticas , Unión Proteica , Proteínas Represoras/metabolismo , Vía de Señalización WntRESUMEN
Infliximab is a promising drug with good outcomes demonstrated for diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and spondyloarthropathy (SpA). However, treatment with this drug may increase the risk of tuberculosis infection. The aim of the present study was to investigate infliximab-associated tuberculosis infection. Literature searches in PubMed, MEDLINE and EMBASE databases were performed. Randomized controlled trials with >95% of the patients >18 years-old were included. Meta-analysis was performed to investigate the incidence of tuberculosis infection after infliximab infusion. A total of 24 RCTs were included in the present meta-analysis. In total, 21 (0.51%) tuberculosis infections were detected among 4,111 patients administered infliximab therapy, compared with 0 (0%) among 2,229 patients assigned to the placebo group. Pooled odds ratio (OR) of developing tuberculosis infection was significantly higher with infliximab therapy than with placebo [2.86; 95% confidence interval (CI), 1.09-7.52]. The OR of tuberculosis infection was 3.93 (95% CI, 0.91-16.91) in RA, 2.46 (95% CI, 0.38-15.92) in SpA and 1.66 (95% CI, 0.26-10.57) in IBD. Rates of tuberculosis infection with infliximab therapy in RA, SpA and IBD were 0.70, 0.22 and 0.52%, respectively. Compared with placebo, infliximab therapy may increase the risk of developing tuberculosis. However, the ORs for the risk of infliximab-associated tuberculosis were not demonstrated to be significant in IBD, RA and SpA; therefore, these findings should be interpreted with caution. The risk of developing tuberculosis demonstrates the importance of the prevention and management of tuberculosis infection with infliximab therapy.
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Gastric cancer stem cells (GCSCs) have an important role in metastasis and recurrence of gastric cancer, and novel treatment strategies that target GCSCs are urgently required. Although evodiamine (Evo), a derivative of the traditional herbal medicine Evodia rutaecarpa, has been reported to have various biological effects, its effect on GCSCs remains unknown. In order to determine the effect of Evo on apoptosis of GCSCs, an MTS assay, flow cytometry and western blot analysis were performed. The effect of Evo on selfrenewal in GCSCs was measured by alterations in the sphere formation ability, the expression of inducedpluripotent stem cell factors, expression of epithelial-to-mesenchymal transition (EMT) factors and oxaliplatin resistance of gastric cancer cells (GCCs). Evo inhibited proliferation, promoted the Bax/Bcell lymphoma 2 ratio and altered active caspase3 expression of GCSCs. In addition, Evo decreased the sphere formation ability, the expression of Sox2, KLF4, Bmi1 and Oct4, and oxaliplatin resistance in GCCs. Evo decreased the expression of Slug, Twist, Zeb1 and vimentin, suggesting an inhibitory effect on EMT. Furthermore, the expression of ßcatenin, cMyc and cyclin D1 was decreased in Evotreated spheroids from GCCs. In conclusion, Evo inhibited the Wnt/ßcatenin signaling pathway to inhibit proliferation and stem cell properties of GCSCs and repressed the EMT. The present findings highlight the prospect of Evo as a CSCs-targeted therapy in gastric cancer.
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Proliferación Celular/efectos de los fármacos , Células Madre Neoplásicas/efectos de los fármacos , Quinazolinas/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ciclina D1/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Citometría de Flujo , Humanos , Factor 4 Similar a Kruppel , Estructura Molecular , Células Madre Neoplásicas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Quinazolinas/química , Factores de Transcripción de la Familia Snail , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Factores de Transcripción/metabolismo , Proteína 1 Relacionada con Twist/metabolismo , Proteína X Asociada a bcl-2/metabolismo , beta Catenina/metabolismoRESUMEN
Nuclear receptors are a superfamily of transcription factors including the steroid hormone receptors, non-steroid hormone receptors and the orphan nuclear receptor family. Retinoic acid-related orphan receptor (ROR)ß, as a member of the orphan nuclear receptor family, plays an important regulatory role in the maintenance of a variety of physiological and pathological processes. RORß has been determined to act as an osteogenic repressor in regulating bone formation, and is involved in regulating circadian rhythm. The findings of recent studies concerning the association between tumorigenesis and circadian rhythm have shown that an aberrant circadian rhythm may promote tumorigenesis and tumor progression. The mechanisms discussed in this review demonstrate how aberrant RORß-induced circadian rhythm may become a new direction for future studies on tumorigenesis and strategy design for cancer prevention.
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Transformación Celular Neoplásica , Trastornos Cronobiológicos , Ritmo Circadiano , Proteínas de Neoplasias/metabolismo , Neoplasias , Miembro 2 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Animales , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Trastornos Cronobiológicos/metabolismo , Trastornos Cronobiológicos/patología , Trastornos Cronobiológicos/fisiopatología , Humanos , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/prevención & controlRESUMEN
Abnormal cytokinesis increases the possibility of nuclear fusion in tumor cells. However, the role of microRNAs (miRNAs) in abnormal cytokinesis is unclear. Here, we found that miR-1290 was significantly up-regulated in clinical colon cancer tissues. Up-regulation of miR-1290 postponed cytokinesis and led to the formation of multinucleated cells. KIF13B was a target of miR-1290 that was involved in aberrant cytokinesis. Furthermore, enforced expression of miR-1290 activated the Wnt pathway and increased the reprogramming-related transcript factors c-Myc and Nanog. Our results suggest that up-regulation of miR-1290 in colon cancer cells impaired cytokinesis and affected reprogramming.
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Adenoma/patología , Neoplasias del Colon/patología , Citocinesis/genética , MicroARNs/genética , Regulación hacia Arriba , Adenoma/genética , Adenoma/metabolismo , Secuencia de Bases , Sitios de Unión , Línea Celular Tumoral , División del Núcleo Celular , Proliferación Celular , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Humanos , Cinesinas/genética , Cinesinas/metabolismo , MicroARNs/metabolismo , MicroARNs/fisiología , FN-kappa B/metabolismo , Proteína Homeótica Nanog , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Interferencia de ARN , Transcripción Genética , Vía de Señalización WntRESUMEN
CagA of Helicobacter pylori is a bacterium-derived oncogenic protein closely associated with the development of gastric cancers. MicroRNAs (miRNAs) are a class of widespread non-coding RNAs, many of which are involved in cell growth, cell differentiation and tumorigenesis. The relationship between CagA protein and miRNAs is unclear. Using mammalian miRNA profile microarrays, we found that miRNA-584 and miRNA-1290 expression was up-regulated in CagA-transformed cells, miRNA-1290 was up-regulated in an Erk1/2-dependent manner, and miRNA-584 was activated by NF-κB. miRNA-584 sustained Erk1/2 activities through inhibition of PPP2a activities, and miRNA-1290 activated NF-κB by knockdown of NKRF. Foxa1 was revealed to be an important target of miRNA-584 and miRNA-1290. Knockdown of Foxa1 promoted the epithelial-mesenchymal transition significantly. Overexpression of miRNA-584 and miRNA-1290 induced intestinal metaplasia of gastric epithelial cells in knock-in mice. These results indicate that miRNA-584 and miRNA-1290 interfere with cell differentiation and remodel the tissues. Thus, the miRNA pathway is a new pathogenic mechanism of CagA.