RESUMEN
Chronic stress may induce learning and memory deficits that are associated with a depression-like state in Drosophila melanogaster. The molecular and neural mechanisms underlying the etiology of chronic stress-induced learning deficit (CSLD) remain elusive. Here, we show that the autophagy-lysosomal pathway, a conserved cellular signaling mechanism, is associated with chronic stress in Drosophila, as indicated by time-series transcriptome profiling. Our findings demonstrate that chronic stress induces the disruption of autophagic flux, and chronic disruption of autophagic flux could lead to a learning deficit. Remarkably, preventing the disruption of autophagic flux by up-regulating the basal autophagy level is sufficient to protect against CSLD. Consistent with the essential role of the dopaminergic system in modulating susceptibility to CSLD, dopamine neuronal activity is also indispensable for chronic stress to induce the disruption of autophagic flux. By screening knockout mutants, we found that neuropeptide F, the Drosophila homolog of neuropeptide Y, is necessary for normal autophagic flux and promotes resilience to CSLD. Moreover, neuropeptide F signaling during chronic stress treatment promotes resilience to CSLD by preventing the disruption of autophagic flux. Importantly, neuropeptide F receptor activity in dopamine neurons also promotes resilience to CSLD. Together, our data elucidate a mechanism by which stress-induced excessive dopaminergic activity precipitates the disruption of autophagic flux, and chronic disruption of autophagic flux leads to CSLD, while inhibitory neuropeptide F signaling to dopamine neurons promotes resilience to CSLD by preventing the disruption of autophagic flux.
Asunto(s)
Drosophila , Neuropéptido Y , Animales , Drosophila melanogaster/genética , Sistema Nervioso , Autofagia/genéticaRESUMEN
ABSTRACT AND AIM: Cholangiocarcinoma (CCA) is a highly aggressive and lethal cancer that originates from the biliary epithelium. Systemic treatment options for CCA are currently limited, and the first targeted drug of CCA, pemigatinib, emerged in 2020 for CCA treatment by inhibiting FGFR2 phosphorylation. However, the regulatory mechanism of FGFR2 phosphorylation is not fully elucidated. APPROACH AND RESULTS: Here we screened the FGFR2-interacting proteins and showed that protein tyrosine phosphatase (PTP) N9 interacts with FGFR2 and negatively regulates FGFR2 pY656/657 . Using phosphatase activity assays and modeling the FGFR2-PTPN9 complex structure, we identified FGFR2 pY656/657 as a substrate of PTPN9, and found that sec. 14p domain of PTPN9 interacts with FGFR2 through ACAP1 mediation. Coexpression of PTPN9 and ACAP1 indicates a favorable prognosis for CCA. In addition, we identified key amino acids and motifs involved in the sec. 14p-APCP1-FGFR2 interaction, including the "YRETRRKE" motif of sec. 14p, Y471 of PTPN9, as well as the PH and Arf-GAP domain of ACAP1. Moreover, we discovered that the FGFR2 I654V substitution can decrease PTPN9-FGFR2 interaction and thereby reduce the effectiveness of pemigatinib treatment. Using a series of in vitro and in vivo experiments including patient-derived xenografts (PDX), we showed that PTPN9 synergistically enhances pemigatinib effectiveness and suppresses CCA proliferation, migration, and invasion by inhibiting FGFR2 pY656/657 . CONCLUSIONS: Our study identifies PTPN9 as a negative regulator of FGFR2 phosphorylation and a synergistic factor for pemigatinib treatment. The molecular mechanism, oncogenic function, and clinical significance of the PTPN9-ACAP1-FGFR2 complex are revealed, providing more evidence for CCA precision treatment.
Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Morfolinas , Pirimidinas , Pirroles , Humanos , Colangiocarcinoma/tratamiento farmacológico , Epitelio , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Conductos Biliares Intrahepáticos , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos , Proteínas Activadoras de GTPasaRESUMEN
Chronic stress could induce severe cognitive impairments. Despite extensive investigations in mammalian models, the underlying mechanisms remain obscure. Here, we show that chronic stress could induce dramatic learning and memory deficits in Drosophila melanogaster The chronic stress-induced learning deficit (CSLD) is long lasting and associated with other depression-like behaviors. We demonstrated that excessive dopaminergic activity provokes susceptibility to CSLD. Remarkably, a pair of PPL1-γ1pedc dopaminergic neurons that project to the mushroom body (MB) γ1pedc compartment play a key role in regulating susceptibility to CSLD so that stress-induced PPL1-γ1pedc hyperactivity facilitates the development of CSLD. Consistently, the mushroom body output neurons (MBON) of the γ1pedc compartment, MBON-γ1pedc>α/ß neurons, are important for modulating susceptibility to CSLD. Imaging studies showed that dopaminergic activity is necessary to provoke the development of chronic stress-induced maladaptations in the MB network. Together, our data support that PPL1-γ1pedc mediates chronic stress signals to drive allostatic maladaptations in the MB network that lead to CSLD.
Asunto(s)
Neuronas Dopaminérgicas/metabolismo , Discapacidades para el Aprendizaje/etiología , Trastornos de la Memoria/etiología , Estrés Fisiológico , Animales , Enfermedad Crónica , Depresión/etiología , Drosophila melanogaster , Olfato/fisiologíaRESUMEN
Optimizing the layout of urban stormwater management systems is an effective method for mitigating the risk of urban flooding under extreme storms. However, traditional approaches that consider only economic costs or annual runoff control rates cannot dynamically respond to the uncertainties of extreme weather, making it difficult to completely avoid large accumulations of water and flooding in a short period. This study proposes an integrated method combining system layout optimization and Model Predictive Control(MPC)to enhance the system's resilience and effectiveness in flood control. An optimization framework was initially built to identify optimal system layouts, balancing annual average life cycle cost (AALCC) and resilience index. The MPC was then applied to the optimal layout selected using the Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) method, aiming to alleviate inundation cost-effectively. The adaptability of MPC to varying sets of control horizons and its efficacy in managing the hydrograph and flood dynamics of urban drainage system were examined. Conducted in Yubei, Chongqing, this study revealed patterns in optimal layout fronts among various extreme design rainfalls, showing that peak position rate and return period significantly influence system resilience. The contribution of MPC to the optimal system layout was particularly notable, resulting in improved instantaneous and overall flood mitigation. The application of MPC increased the resilience index by an average of 0.0485 and offered cost savings of 0.0514 million yuan in AALCC. Besides, our findings highlighted the importance of selecting an optimal set of control horizons for MPC, which could reduce maximum flood depth from 0.43m to 0.19m and decrease conduit peak flow by up to 14% at a flood-prone downstream location.
Asunto(s)
Inundaciones , Modelos Teóricos , Lluvia , Movimientos del AguaRESUMEN
BACKGROUND: Stage II/III disease is the most predominant form of colorectal cancer, accounting for approximately 70% of cases. Furthermore, approximately 15% to 20% of patients with stage II/III disease have deficient mismatch repair or microsatellite instability-high colorectal cancer. However, there are no identified significant prognostic biomarkers for this disease. OBJECTIVE: To identify prognostic markers for patients with deficient mismatch repair/microsatellite instability-high colon cancer stage II/III. DESIGN: Retrospective study design. SETTING: The study was conducted at a high-volume colorectal center, the Cancer Hospital, Chinese Academy of Medical Sciences. PATIENTS: Patients diagnosed with stage II/III deficient mismatch repair/microsatellite instability-high colon cancer who underwent curative surgery at the Cancer Hospital at the Chinese Academy of Medical Sciences between July 2015 and November 2018 were included. MAIN OUTCOME MEASURES: The primary outcome measure was the influence of differentially mutated genes on progression-free survival. RESULTS: The retrospective deficient mismatch repair/microsatellite instability-high cohort involved 32 patients and The Cancer Genome Atlas-microsatellite instability-high cohort involved 45 patients. Patients with deficient mismatch repair/microsatellite instability-high colon cancer had higher mutational frequencies of MKI67 , TPR , and TCHH than patients with microsatellite stable colon cancer. MKI67 , TPR , TCHH , and gene combination were significantly correlated with prognosis. The biomarker mutation-type colon cancer group had a higher risk of recurrence or death than did the wild-type group. Moreover, biomarker mutation-type tumors had more mutations in the DNA damage repair pathway and tumor mutational burden than did biomarker wild-type tumors. LIMITATIONS: This study was limited by its retrospective nature. CONCLUSIONS: MKI67 , TPR , and TCHH may serve as potential diagnostic and prognostic biomarkers for deficient mismatch repair/microsatellite instability-high colon cancer stage II/III. IDENTIFICACIN DE MUTACIONES MKI, TPR Y TCHH COMO BIOMARCADORES PRONSTICOS PARA PACIENTES CON CNCER DE COLON EN ETAPA II/III CON DEFICIENCIA EN LA REPARACION DE ERRORES DE EMPAREJAMIENTO: ANTECEDENTES:La enfermedad en estadio II/III es la forma más predominante de cáncer colorrectal y representa aproximadamente el 70% de los casos. Además, aproximadamente entre el 15% y el 20% de los pacientes con enfermedad en estadio II/III tienen reparación deficiente de errores de emparejamiento o inestabilidad de microsatélital alta. Sin embargo, no se han identificado biomarcadores pronósticos significativos para esta enfermedad.OBJETIVO:Este estudio tuvo como objetivo identificar marcadores pronósticos para pacientes con cáncer de colon con reparación deficiente de errores de emparejamiento/inestabilidad microsatelital alta en estadio II/III.DISEÑO:Diseño de estudio retrospectivo.ESCENARIO:El estudio se realizó en un centro colorrectal de alto volumen, el Hospital del Cáncer de la Academia China de Ciencias Médicas.PACIENTES:Pacientes diagnosticados con cáncer de colon en estadio II/III con reparación deficiente de errores de emparejamiento o inestabilidad de microsatélital alta que se sometieron a cirugía curativa en el Hospital del Cáncer de la Academia China de Ciencias Médicas entre julio de 2015 y noviembre de 2018.MEDIDAS DE RESULTADO PRINCIPALES:La medida de resultado primaria fue la influencia de los genes con mutaciones diferenciales en la supervivencia libre de progresión.RESULTADOS:La cohorte retrospectiva de reparación deficiente de errores de emparejamiento o inestabilidad de microsatélital alta y la cohorte de inestabilidad microsatelital alta del Atlas del Genoma del Cáncer involucraron a 32 y 45 pacientes, respectivamente. Los pacientes con de reparación deficiente de errores de emparejamiento/inestabilidad microsatélital alta tuvieron frecuencias mutacionales más altas de MKI67 , TPR y TCHH que los pacientes estables de microsatélites. MKI67 , TPR , TCHH , y la combinación de genes se correlacionaron significativamente con el pronóstico. El grupo de cáncer de colon de tipo mutación de biomarcador tenía un mayor riesgo de recurrencia o muerte que el grupo de mutación salvaje. Además, los tumores de tipo mutación de biomarcadores tenían más mutaciones en la vía de reparación del daño del ADN y la carga mutacional del tumor que los tumores de tipo salvaje de biomarcadores.LIMITACIONES:Este estudio estuvo limitado por su naturaleza retrospectiva.CONCLUSIONES:MKI67 , TPR , y TCHH pueden servir como posibles biomarcadores de diagnóstico y pronóstico para cáncer de colon en estadio II/III con reparación deficiente de errores de emparejamiento/inestabilidad microsatélital alta. (Traducción-Dr. Jorge Silva Velazco ).
Asunto(s)
Neoplasias del Colon , Reparación de la Incompatibilidad de ADN , Humanos , Antígenos , Neoplasias del Colon/genética , Neoplasias del Colon/cirugía , Reparación de la Incompatibilidad de ADN/genética , Proteínas de Filamentos Intermediarios , Inestabilidad de Microsatélites , Mutación , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Antígeno Ki-67/genéticaRESUMEN
BACKGROUND: Cholangiocarcinoma (CCA) is a class of malignant tumors originating from bile duct epithelial cells. Due to difficult early diagnosis and limited treatment, the prognosis of CCA is extremely poor. BMI1 is dysregulated in many human malignancies. However, the prognostic significance and oncogenic role of BMI1 in cholangiocarcinoma (CCA) are not well elucidated. METHODS: In the present study, we investigated its clinical importance and the potential mechanisms in the progression of CCA. We detected BMI1 expression in a large CCA cohort. We demonstrated that BMI1 was substantially upregulated in CCA tissues and was identified as an independent prognostic biomarker of CCA. Moreover, overexpression of BMI1 promoted CCA proliferation, migration, and invasion. And BMI1 knockdown could inhibit proliferation and metastases of CCA in vitro and in vitro/vivo validation. Interestingly, we found that CCA-derived exosomes contain BMI1 proteins, which can transfer BMI1 between CCA cells. The unique BMI1-containing exosomes promote CCA proliferation and metastasis through autocrine/paracrine mechanisms. In addition, we demonstrated that BMI1 inhibits CD8+T cell-recruiting chemokines by promoting repressive H2A ubiquitination in CCA cells. CONCLUSIONS: BMI1 is an unfavorable prognostic biomarker of CCA. Our data depict a novel function of BMI1 in CCA tumorigenesis and metastasis mediated by exosomes. Besides, BMI1 inhibition may augment immune checkpoint blockade to inhibit tumor progression by activating cell-intrinsic immunity of CCA.
Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Exosomas , Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Biomarcadores , Carcinogénesis , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Exosomas/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismoRESUMEN
Cholangiocarcinoma (CCA) is a highly aggressive malignancy with extremely poor prognoses. The oncogenic role and prognostic value of c-Myc in CCA is not well elucidated. WD repeat domain 5 (WDR5) is a critical regulatory factor directly interacting with c-Myc to regulate c-Myc recruitment at chromosomal locations, but the interaction of WDR5 and c-Myc in CCA was uncovered. In our study, we detected WDR5 and c-Myc expression in all CCA types, including intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) CCA, and evaluated their prognostic significance. Consequently, we demonstrated that WDR5 was significantly correlated with poor prognosis of CCA and that WDR5 and c-Myc co-expression was a more sensitive prognostic factor. With in vitro and in vivo experiments and bioinformatics, we showed that WDR5 interacted with the Myc box IIIb (MBIIIb) motif of c-Myc and facilitated Myc-induced HIF1A transcription, thereby promoting the epithelial-mesenchymal transition (EMT), invasion, and metastasis of CCA. Moreover, WDR5 enhanced hypoxia-inducible factor 1 subunit α (HIF-1α) accumulation by binding with histone deacetylase 2 (HDAC2) and increasing histone 3 lysine 4 acetylation (H3K4ac) deacetylation of the prolyl hydroxylase domain protein 2 (PHD2) promoter, resulting in the attenuation of chromatin opening and PHD2 expression, and eventually leading to HIF-1α stabilization and accumulation. In conclusion, WDR5 facilitated EMT and metastasis of CCA by increasing HIF-1α accumulation in a Myc-dependent pathway to promote HIF-1α transcription and a Myc-independent pathway to stabilize HIF-1α.
Asunto(s)
Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Transición Epitelial-Mesenquimal/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal , Acetilación , Animales , Biomarcadores de Tumor , Línea Celular Tumoral , Colangiocarcinoma/mortalidad , Colangiocarcinoma/patología , Modelos Animales de Enfermedad , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Xenoinjertos , Histonas , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , PronósticoRESUMEN
Epilepsy treatment with antiepileptic drugs (AEDs) is usually requires for many years. Q808 is an innovative antiepileptic chemical. It exerts effective antiepileptic effect against various epilepsy models. Exploring the gene transcriptomic profile of long-term treatment of Q808 is necessary. In the present study, hippocampus RNA-sequencing was performed to reveal the transcriptome profile of rats before and after treatment of Q808 for 28 d. Results confirmed 51 differentially expressed genes (DEGs) between Q808 and healthy control groups. Gene cluster analysis showed that most upregulated DEGs linked to response to drug and nucleus, most downregulated DEGs linked to locomotory, neuronal cell body, and drug binding. Most of DEGs were enriched in the signaling transduction, substance dependence, nervous system, and neurodegenerative disease pathways. Furthermore, quantitative real-time PCR analysis confirmed that Q808 significantly increased the expression of neuroprotective genes, such as Mdk, and decreased the mRNA levels of Penk, Drd1, and Adora2a, which are highly expressed in epilepsy models. In addition, Q808 decreased the mRNA expression of Pde10A and Drd2, which are known to be closely associated with schizophrenia. Our study may provide a theoretical basis to explore the effect of Q808 on the susceptibility to epilepsy and other neurological diseases.
Asunto(s)
Epilepsia , Enfermedades Neurodegenerativas , Animales , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Perfilación de la Expresión Génica , Hipocampo/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , ARN Mensajero/genética , Ratas , TranscriptomaRESUMEN
The chemical constituents from lipophilic parts in the roots of Angelica dahurica var. formosana cv. Chuanbaizhi were studied in this paper. The compounds were separated and purified by repeated column chromatographic methods on silica gel and HPLC, and the chemical structures of compounds were determined by spectral data analyses. Twenty-nine compounds were obtained and identified as isoimperatorin (1), ß-sitosterol (2), imperatorin (3), bergapten (4), osthenol (5), xanthotoxin (6), isoimpinellin (7), dehydrogeijerin (8), phellopterin (9), isodemethylfuropinarine (10), 7-demethylsuberosin (11), alloimperatorin (12), xanthotoxol (13), isooxypeucedanin (14), alloisoimperatorin (15), demethylfuropinarine (16), 5-hydroxy-8-methoxypsoralen (17), oxypeucedanin methanolate (18), pabulenol (19), byakangelicin (20), marmesin (21), (+) -decursinol (22), heraclenol (23), oxypeucedanin hydrate (24), marmesinin (25), ulopterol (26), erythro-guaiacylglycerol-ß-ferulic acid ether (27), threo-guaiacylglycerol-ß-ferulic acid ether (28), and uracil (29). Compounds 5, 8, 11, 18, 21-23, and 26-28 were obtained from the roots of title plant for the first time.
Asunto(s)
Angelica/química , Fitoquímicos/análisis , Cumarinas/química , Cumarinas/aislamiento & purificación , Furocumarinas/química , Furocumarinas/aislamiento & purificación , Metoxaleno/química , Metoxaleno/aislamiento & purificación , Fitoquímicos/química , Raíces de Plantas/químicaRESUMEN
Cutaneous squamous cell carcinoma (CSCC) is a severe malignancy derived from the skin. Circular RNAs (circRNAs) play an important role in the pathological process of many malignant tumors. Moreover, circIFFO1 is reported to be down-regulated in CSCC tissues compared with non-lesional skin tissues. This study aimed to explore the specific role and potential mechanism of circIFFO1 in CSCC progression. Cell proliferation ability was analyzed by 3-(4, 5-dimethylthiazol-2-y1)-2,5-diphenyl tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU) incorporation, and colony-formation assays. Cell cycle progression and apoptosis were detected by flow cytometry. Cell migration and invasion were examined by transwell assays. The interaction between microRNA-424-5p (miR-424-5p) and circIFFO1 or nuclear factor I/B (NFIB) was validated by dual-luciferase reporter, RNA pull-down, and RNA immunoprecipitation (RIP) assays. Xenograft tumor assay and immunohistochemistry (IHC) assay were employed to analyze the tumorigenesis in vivo. CircIFFO1 level was down-regulated in CSCC tissues and cell lines. CircIFFO1 overexpression suppressed the proliferation, migration, invasion, and promoted apoptosis of CSCC cells. CircIFFO1 acted as a molecular sponge for miR-424-5p. The anti-tumor effects mediated by circIFFO1 overexpression in CSCC cells could be reversed by miR-424-5p overexpression. miR-424-5p interacted with the 3' untranslated region (3'UTR) of Nuclear Factor I/B (NFIB). miR-424-5p knockdown suppressed the malignant behaviors of CSCC cells, and NFIB knockdown counteracted the anti-tumor effects of miR-424-5p absence in CSCC cells. Additionally, circIFFO1 overexpression restrained xenograft tumor growth in vivo. CircIFFO1 suppressed the malignant behaviors of CSCC by mediating the miR-424-5p/NFIB axis, which provided new insights into the pathogenesis of CSCC.
Asunto(s)
Carcinoma de Células Escamosas , MicroARNs , Neoplasias Cutáneas , Humanos , Regiones no Traducidas 3' , Carcinogénesis , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Proliferación Celular , MicroARNs/genética , Factores de Transcripción NFI , Neoplasias Cutáneas/genéticaRESUMEN
Natural products play important roles in the pathogenesis of many human malignancies, including colorectal cancer, and can act as a gene regulator in many cancers. They regulate malignant cell growth through many cellular signal pathways, including Rac family small GTPase 1 (RAC1)/PI3K/AKT (α-serine/threonine-protein kinase), mitogen-activated protein kinase (MAPK), Wnt/ß-catenin pathway, transforming growth factor-ß (TGF-ß), Janus kinase and signal transducer and activator of transcription (JAK-STAT), nuclear factor kappa-B (NF-κB), the Notch pathway, Hippo pathway, and Hedgehog pathway. In this review, we describe the epigenetic roles of several natural products, e.g., platycodin D (PD), ginsenoside Rd, tretinoin, Rutin, curcumin, clove extract, betulinic acid, resveratrol, and curcumin, in colorectal cancer, including their impact on colorectal cancer cell proliferation, apoptosis, invasion, migration, and anti-chemotherapeutic resistance. The aim is to illustrate the epigenetic mechanisms of action of natural products in cancer prevention and treatment, and to provide (1) a theoretical basis for the study of the role of epigenetics in influencing colorectal cancer; (2) new directions for studying the occurrence, development, and prognosis of colorectal cancer; and (3) new targets for treating and preventing colorectal cancer.
RESUMEN
Regeneration is a complex process affected by many elements independent or combined, including inflammation, proliferation, and tissue remodeling. Stem cells is a class of primitive cells with the potentiality of differentiation, regenerate with self-replication, multidirectional differentiation, and immunomodulatory functions. Stem cells and their cytokines not only inextricably linked to the regeneration of ectodermal and skin tissues, but also can be used for the treatment of a variety of chronic wounds. Stem cells can produce exosomes in a paracrine manner. Stem cell exosomes play an important role in tissue regeneration, repair, and accelerated wound healing, the biological properties of which are similar with stem cells, while stem cell exosomes are safer and more effective. Skin and bone tissues are critical organs in the body, which are essential for sustaining life activities. The weak repairing ability leads a pronounced impact on the quality of life of patients, which could be alleviated by stem cell exosomes treatment. However, there are obstacles that stem cells and stem cells exosomes trough skin for improved bioavailability. This paper summarizes the applications and mechanisms of stem cells and stem cells exosomes for skin and bone healing. We also propose new ways of utilizing stem cells and their exosomes through different nanoformulations, liposomes and nanoliposomes, polymer micelles, microspheres, hydrogels, and scaffold microneedles, to improve their use in tissue healing and regeneration.
RESUMEN
Liver metastasis is the main cause of death in patients with colorectal cancer (CRC); thus, necessitating effective biomarkers and therapeutic targets for colorectal cancer liver metastasis (CRLM). Fibroblast growth factor 19 (FGF19) is a protumorigenic gene in numerous human malignancies. In this study, it is shown that FGF19 plays an indispensable role in CRLM. FGF19 expression and secretion are markedly correlated with liver metastasis and lower overall survival rates of patients with CRC. An in vivo metastasis model shows that FGF19 overexpression confers stronger liver-metastatic potential in CRC cells. Mechanistically, FGF19 exerts an immunomodulatory function that creates an environment conducive for metastasis in CRLM. FGF19 mediates the polarization of hepatic stellate cells to inflammatory cancer-associated fibroblasts (iCAFs) by activating the autocrine effect of IL-1α via the FGFR4-JAK2-STAT3 pathway. FGF19-induced iCAFs promote neutrophil infiltration and mediate neutrophil extracellular trap (NET) formation in liver metastatic niches via the production of complement C5a and IL-1ß, which in turn accelerates the liver colonization of CRC cells. Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19-induced liver metastasis in a mouse model. In summary, this study describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention.
Asunto(s)
Neoplasias Colorrectales , Trampas Extracelulares , Neoplasias Hepáticas , Animales , Ratones , Humanos , Trampas Extracelulares/metabolismo , Línea Celular Tumoral , Neoplasias Hepáticas/metabolismo , Transducción de Señal , Neoplasias Colorrectales/genética , Factores de Crecimiento de Fibroblastos/metabolismoRESUMEN
Biological effects of magnetic fields have been extensively studied in plants, microorganisms and animals, and applications of magnetic fields in regulation of plant growth and phytoprotection is a promising field in sustainable agriculture. However, the effect of magnetic fields especially ultra-high static magnetic field (UHSMF) on genomic stability is largely unclear. Here, we investigated the mutagenicity of 24.5, 30.5 and 33.0 T UHSMFs with the gradient of 150, 95 and 0 T/m, respectively, via whole genome sequencing. Our results showed that 1 h exposure of Arabidopsis dried seeds to UHSMFs has no significant effect on the average rate of DNA mutations including single nucleotide variations and InDels (insertions and deletions) in comparison with the control, but 33.0 T and 24.5 T treatments lead to a significant change in the rate of nucleotide transitions and InDels longer than 3 bp, respectively, suggesting that both strength and gradient of UHSMF impact molecular spectrum of DNA mutations. We also found that the decreased transition rate in UHSMF groups is correlated with the upstream flanking sequences of G and C mutation sites. Furthermore, the germination rate of seeds exposed to 24.5 T SMF with -150 T/m gradient showed a significant decrease at 24 hours after sowing. Overall, our data lay a basis for precisely assessing the potential risk of UHSMF on DNA stability, and for elucidating molecular mechanism underlying gradient SMF-regulated biological processes in the future.
RESUMEN
Background: Radiation therapy (RT) is a crucial modality for the local control of pelvic cancer (PC), but the effect of pelvic RT on the development of secondary malignancy is still unclear. This study aimed to identify the relationship between radiation therapy received for the treatment of primary PC and subsequent secondary bladder cancer (SBC). Methods: The Surveillance, Epidemiology, and End Results (SEER) database (from 1975 to 2015) was queried for PC. Fine-gray competing risk regression and Cox regression analyses were employed to assess the cumulative incidence of SBC. Poisson regression and multiple primary standardized incidence ratios (SIR) were used to evaluate the radiotherapy-associated risk for patients receiving RT. Subgroup analyses of patients stratified by latency time since PC diagnosis, calendar year of PC diagnosis stage, and age at PC diagnosis were also performed. Overall survival (OS) was compared among different treatment groups with SBC by Kaplan-Meier analysis. Results: A total of 318,165 observations showed that the primary cancers were located in pelvic cavity, 256,313 patients did not receive radiation therapy (NRT), 51,347 patients who underwent external beam radiation therapy (EBRT), and 10,505 patients receiving a combination of EBRT and brachytherapy (EBRT-BRT) who developed SBC. Receiving two types of radiotherapy was strongly consistent with a higher risk of developing SBC for PC patients in Fine-Gray competing risk regression (NRT vs. EBRT, adjusted HR= 1.71, 95% CI: 1.54-1.90, P<0.001; NRT vs. EBRT-BRT, adjusted HR= 2.16, 95% CI: 1.78-2.63, P<0.001). The results of the dynamic SIR and Poisson regression analysis for SBC revealed that a slightly increased risk of SBC was observed after RT in the early latency and was significantly related to the variations of age at PC diagnosis and decreased with time progress. For OS, the SBC after NRT, SBC after EBRT, and SBC after EBRT-BRT of 10-year survival rates were 37.9%, 29.2%, and 22.2%, respectively. Conclusion: Radiotherapy for primary PC was associated with higher risks of developing SBC than patients unexposed to radiotherapy. Different pelvic RT treatment modalities had different effects on the risk of SBC.
RESUMEN
Background: Radiation therapy (RT) is a standard treatment for the local control of primary pelvic cancers (PPC), yet the risk of second corpus uteri cancer (SCUC) in PPC patients undergoing RT is still controversial. This study investigated the impact of RT on the risk of SCUC and assessed the survival outcome. Methods: We queried nine cancer registries for PPC cases in the Surveillance, Epidemiology, and End Results (SEER) database. The cumulative incidence of SCUC was analyzed using Cox regression and Fine-Gray competing risk regression analysis. The Poisson regression analysis was employed to assess the standardized incidence ratios (SIRs) and radiation-attributed risk (RR) for SCUC. We evaluated the overall survival of patients with SCUC using the Kaplan-Meier method. Results: Receiving radiotherapy was strongly associated with a higher risk of developing SCUC for PPC patients in Fine-Gray competing risk regression (No-RT vs. RT: adjusted HR = 1.77; 95% CI, 1.40-2.28; p < 0.001). The incidence of SCUC in PPC patients who received RT was higher than in the US general population (SIR, 1.66; 95% CI, 1.41-1.93; p < 0.05), but the incidence of SCUC in patients who did not receive RT was lower than with the US general population (SIR, 0.68; 95% CI, 0.61-0.75; p < 0.05). The dynamic SIR and RR for SCUC decreased with decreasing age at PPC diagnosis and decreased with time progress. In terms of overall survival, 10-year survival rates with SCUC after No-RT (NRT) and SCUC after RT were 45.9% and 25.9% (HR = 1.82; 95% CI, 1.46-2.29; p < 0.001), respectively. Conclusion: Radiotherapy for primary pelvic cancers is associated with a higher risk of developing SCUC than patients unexposed to radiotherapy. We suggest that patients with pelvic RT, especially young patients, should receive long-term monitoring for the risk of developing SCUC.
RESUMEN
Our study aims at developing an interferon-stimulated genes (ISGs) signature that could predict overall survival (OS) in cancer patients, which enrolled a total of 5643 pan-cancer patients. Linear models for microarray data method analysis were conducted to identify the differentially expressed prognostic genes in the global ISGs family. Time-dependent receiver operating characteristic (ROC) and Kaplan-Meier survival analysis were used to test the efficiency of a multi-gene signature in predicting the prognosis of pan-cancer patients. The prognostic performance and potential biological function of gene signature were verified by quantitative real-time PCR in a pan-cancer independent cohort. Three ISGs genes were finally identified to build a classifier, a specific risk score formula, with which patients were classified into the low- or high-risk groups. Time-dependent ROC analyses proved prognostic accuracy. Then, its prognostic value was validated in seven external validation series. A nomogram was constructed to guide the individualized treatment of patients with lung adenocarcinoma. Biological pathway and tumor immune infiltration analysis showed that the signature might cause poor prognosis by blocking NK cell activation. Finally, the signature in our centers was confirmed by real-time quantitative PCR. A robust ISGs-related feature was discovered to effectively classify pan-cancer patients into subgroups with different OS.
Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Humanos , Interferones/genética , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , PronósticoRESUMEN
Background: The type 2 mannose receptor C (MRC2) is involved in tumor biological processes and plays a new role in the remodeling of the extracellular matrix turnover. Previous studies have demonstrated MRC2 expression profiling and prognostic relevance in some tumor types. However, the clinical and immunotherapeutic value of MRC2 in pan-cancers remains controversial. Our study aimed to evaluate MRC2 expression pattern, clinical characteristics and prognostic significance in 33 cancers, explore the relationship between MRC2 and immune-related characteristics, and assess the prediction of MRC2 for the immunotherapeutic response. Methods: Transcriptional and clinical data of 33 cancers were downloaded from The Cancer Genome Atlas database (TCGA) database and two independent immunotherapeutic cohorts were obtained from GSE67501 and the IMvigor210 study. Next, patients stratified by MRC2 expression levels were displayed by Kaplan-Meier plot to compare prognosis-related indexes. Meanwhile, immune infiltrates of different cancers were estimated by tumor immune estimation resources (TIMER) and CIBERSORT. The ESTIMATE algorithm was used to estimate the immune and stromal scores in tumor tissues. MRC2 expression and immunological modulators, including immune inhibitors, immune stimulators, and MHC molecules, were screened through the TISIDB portal. Gene-set enrichment analysis analyses were performed to explore the underlying biological process of MRC2 across different cancers. The immunotherapeutic response prediction was performed in two independent cohorts (GSE78220: metastatic melanoma with pembrolizumab treatment and IMvigor210: advanced urothelial cancer with atezolizumab intervention). Results: MRC2 is expressed differently in many cancers and has been shown to have potential prognostic predicting significance. MRC2 was significantly associated with immune cell infiltration, immune modulators, and immunotherapeutic markers. Notably, the immunotherapeutic response group was associated with lower MRC2 expression in metastatic melanoma and advanced urothelial carcinoma cohort. Conclusion: This study demonstrated that MRC2 could be a prognostic indicator for certain cancer and is critical for tumor immune microenvironments. MRC2 expression level may influence and predict immune checkpoint blockade response as a potential indicator.
RESUMEN
Cholangiocarcinoma (CCA), consisting of three subtypes-intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA), is a highly aggressive cancer arising from the bile duct and has an extremely poor prognosis. Pemigatinib is the only FDA-approved targeted drug for CCA, and the CCA treatment options are substantially insufficient considering its poor prognosis and increasing morbidity. Here, we performed next-generation sequencing (NGS) of 15 pCCAs and 16 dCCAs and detected the expression of SMAD4, a frequently mutated gene, in 261 CCAs. By univariate and multivariate analyses, we identified Smad4 as a favorable prognostic biomarker in iCCA and pCCA. With in vitro and in vivo experiments, we demonstrated that Smad4 suppressed CCA proliferation, migration and invasion by inhibiting ß-catenin-S675 phosphorylation and intranuclear translocation. We applied LC-MS/MS and multiple biochemical techniques and identified PP1A as the phosphatase in Smad4-mediated dephosphorylation of PAK1-T423, which is responsible for ß-catenin-S675 phosphorylation. Moreover, we demonstrated that MYO18A is the PP1-interacting protein of PP1A for substrate recognition in CCA. MYO18A interacts with PP1A via its RVFFR motif and interacts with Smad4 via CC domain. Patients with coexpression of MYO18A and Smad4 have a more favorable prognosis than other patients. Smad4 enhances Pemigatinib efficiency, and Smad4 knockdown results in Pemigatinib resistance. In conclusion, coexpression of Smad4 and MYO18A is a favorable prognostic indicator for iCCA and pCCA. The Smad4-MYO18A-PP1A complex dephosphorylates PAK1-T423 and thus inhibits ß-catenin-S675 phosphorylation and its intranuclear localization. Smad4 suppresses CCA proliferation, migration, invasion, and sensitivity to Pemigatinib by governing the phosphorylation and intracellular localization of ß-catenin.
Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/genética , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , Cromatografía Liquida , Humanos , Morfolinas , Miosinas/metabolismo , Fosforilación , Pirimidinas , Pirroles , Proteína Smad4/metabolismo , Espectrometría de Masas en Tándem , beta Catenina/metabolismo , Quinasas p21 Activadas/genética , Quinasas p21 Activadas/metabolismoRESUMEN
Cholangiocarcinoma (CCA) is a type of highly malignant tumor originating from bile ducts. The prognosis of CCA is poor and the treatment options are limited. The biomarker study of CCA has made little progresses in recent years because of the difficulty to obtain CCA specimens. SOX9 is an important regulator of cholangiocyte proliferation and differentiation. We performed mRNA sequencing of CCA, retrieved TCGA data, and detected SOX9 expression in a large CCA cohort. With WNT3A stimulation, SOX9 expression and transcription was elevated by TCF7. Moreover, SOX9 was substantially up-regulated in CCA tissues and was identified as a prognostic biomarker of CCA. With mRNA sequencing and in vitro/vivo validation, we demonstrated that SOX9 enhanced the transcription and expression of FGF7 and FGFR2. FGF7 was significantly up-regulated in the bile and serum of CCA patients, and may promote CCA proliferation by activating FGFR2 in an autocrine pathway. co-expression of FGF7 and FGFR2 was a more sensitive marker for poor prognosis. SOX9-induced overexpression of FGF7 and FGFR2 was the key reason of SOX9-involved pemigatinib resistance. In conclusion, SOX9 and FGF7 were prognostic biomarkers of CCA. WNT3A-TCF7-SOX9 axis could induce pemigatinib resistance in two independent pathways: (1)SOX9 directly promotes FGFR2 transcription and expression; (2)SOX9 elevates FGF7 expression, which could be secreted from CCA cells and activates FGFR2 phosphorylation in an autocrine pathway.