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1.
Zhonghua Bing Li Xue Za Zhi ; 49(2): 162-167, 2020 Feb 08.
Artículo en Chino | MEDLINE | ID: mdl-32074730

RESUMEN

Objective: To establish patient derived xenograft (PDX) model of malignant peritoneal mesothelioma (MPM), and to identify the key characteristics of tumor biology of the model, so as to provide an experiment platform for studying the pathologic mechanisms and new therapeutic strategies for MPM. Methods: Surgically excised MPM tumor tissues were inoculated subcutaneously in BALB/c-nu/nu mice for 3 stable passages. In the 4th passage, the subcutaneous tumors were harvested under aseptic conditions, cleaned and made into MPM tumor cell homogenate. Four nude mice (two males and two females) were selected and one male and one female nude mouse were inoculated in the abdominal cavity at the dose of 100 µL, others were inoculated at a dose of 200 µL. The PDX model of MPM was established. The changes of body mass in nude mice were measured regularly, the extent of abdominal and pelvic tumors was judged by experimental peritoneal cancer index (ePCI) score, and the pathologic characteristics of tumors were analyzed. Results: The subcutaneous and abdominal animal models of MPM were successfully established. The subcutaneous tumor model grew into tumor on the 20th day, followed by a slow growth stage between the 20th and 29th day, then a rapid growth stage between the 30th and 57th day. According to the dose of tumor cells (100, 200 µL) and timing (14th and 69th days after grafting), the abdominal tumor model successfully simulated the early and late clinical stages of MPM. The HE staining results of the MPM nude mice model showed that the tumor was epithelial mesothelioma and invaded most of the organs, including liver, spleen, pancreas, mesentery. Immunohistochemical staining for calretinin, cytokeratin 5/6, WT1 and Ki-67 were positive. Whole-genome exon sequencing identified 26 and 36 high frequency gene mutations in tumors derived from the PDX model and clinical sample from patients, including 21 common gene mutations. Conclusions: The PDX model of MPM is established. The model is characterized by highly malignant tumor with rapid growth and high invasiveness.


Asunto(s)
Neoplasias Pulmonares , Mesotelioma , Neoplasias Pleurales , Animales , Línea Celular Tumoral , Femenino , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 267-274, 2020 Feb.
Artículo en Chino | MEDLINE | ID: mdl-32027288

RESUMEN

OBJECTIVE: To investigate the effects of human amniotic mesenchymal stem cell(AMSC) on acute graft-versus-host disease (aGVHD) in xenotransplatation. METHODS: NPG mice were injected with human PBMNC via tail vein to establish a xenografted aGVHD model. The mice in the experimental group were divided into PBMNC infusion group and PBMNC+AMSC co-infusion group, the general condition, survival time and manifestations of aGVHD were observed, the body weight and blood routine indicators were detected, the pathological changes of aGVHD target organs (lung, liver, spleen, small intestine) were observed by HE staining, and the levels of human T cells in peripheral blood, tissues and organs of mice was detected by flow cytometry. RESULTS: The manifestations of aGVHD (lassitude hunchback, shrub, weight reduction, etc.) and the pathological damage of the target organs (lung, liver, spleen, intestine) in PBMNC+AMSC co-infusion group were lighter than those in PBMNC infusion group. Moreover, the PBMNC and AMSC co-infusion significantly reduced the implantion proportion of human T lymphocytes (CD3+, CD45+) in mice and increased the ratio of CD4+/CD8+. CONCLUSION: Infusion of human-derived AMSC can attenuate the manifestations of aGVHD in mouse xenografts to a certain level, and improve the pathological damage of receptor target organs.


Asunto(s)
Enfermedad Injerto contra Huésped , Células Madre Mesenquimatosas , Enfermedad Aguda , Animales , Xenoinjertos , Humanos , Ratones , Linfocitos T , Trasplante Heterólogo
4.
Life Sci ; 248: 117467, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32105706

RESUMEN

BACKGROUND: NQO1 protein acts as a cellular protective system, on account of its role as a quinone reductase and redox regulator. Nonetheless, new NQO1 roles are emerging-including its regulation of the cellular proliferation of many tumor cells-and this enzyme has been found to relate to the incidence of various diseases, including chronic myeloid leukemia. However, the mechanisms through which NQO1 influences leukemia progression remain unclear. MARTIAL AND METHODS: The current study looks to name NQO1 as a novel molecular target that modulates DNA synthesis and chronic myeloid leukemia growth. RESULTS AND CONCLUSION: Our results indicate that the frequency of the T allele of NQO1 polymorphism in chronic myeloid leukemia patients is higher than that among healthy East Asian individuals (0.492 vs. 0.419) and much higher than the average level of the general population (0.492 vs. 0.289) (1000 Genomes). Functionally, NQO1 knockdown increases the protein expression of the TOP2A and MCM complex, and consequently promotes DNA synthesis and K562 cell growth. NQO1 knockdown also promotes tumorigenesis in a xenograft model. NQO1 overexpression, on the other hand, was found to have the opposite effects. SIGNIFICANCE: Our results show that NQO1 downregulation promotes K562 cellular proliferation via the elevation of DNA synthesis.


Asunto(s)
ADN de Neoplasias/genética , Regulación Leucémica de la Expresión Génica , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucocitos/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/genética , Adulto , Alelos , Animales , Grupo de Ascendencia Continental Asiática , Línea Celular Tumoral , Proliferación Celular , ADN-Topoisomerasas de Tipo II/genética , ADN-Topoisomerasas de Tipo II/metabolismo , ADN de Neoplasias/biosíntesis , Femenino , Xenoinjertos , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/etnología , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucocitos/patología , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , NAD(P)H Deshidrogenasa (Quinona)/antagonistas & inhibidores , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/genética , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Polimorfismo Genético , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal
5.
J Cancer Res Clin Oncol ; 146(2): 329-342, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31912229

RESUMEN

PURPOSE: Members of the aaRS (aminoacyl-tRNA synthetase) family are proteins controlling the aminoacylation process, in which YARS (tyrosyl-tRNA synthetase) catalyzes the binding of tyrosine to its cognate tRNA and plays an important role in basic biosynthesis. Several studies have demonstrated the association between YARS mutation and certain developmental abnormalities/diseases, yet YARS's linkage with cancer remains uncategorized. In this study, by combining in silico, in vitro, and in vivo studies, we explored the expressions and functions of YARS in gastric cancer (GC). METHODS: We evaluated YARS's distribution in tumor and paired normal tissues/specimens of GC by referring to large cohort online datasets and patient-derived tissue specimens. YARS-related changes were assessed by phenotypical/molecular experiments and RNA-sequencing analysis in GC cell lines harboring YARS knockdown or overexpression. RESULTS: Both the transcript and protein levels of YARS were evidently higher in gastric cancer tissues than in paired normal tissues. YARS knockdown induced repressed proliferation and invasiveness, as well as enhanced apoptosis in GC cell lines, while abnormally upregulating YARS expression promoted gastric cancer growth in vivo. We inferred based on RNA-sequencing that YARS modulates multiple cancerous signaling pathways and proved through cellular experiments that YARS promoted GC progression, as well as homologous recombination by activating PI3K-Akt signaling. CONCLUSIONS: By revealing the existence of a YARS-PI3K-Akt signaling axis in gastric cancer, we discovered that tRNA synthetase YARS is a novel tumorigenic factor, characterized by its upregulation in tumor-derived specimens, as well as its functions in promoting gastric cancer progression.


Asunto(s)
Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Gástricas/enzimología , Tirosina-ARNt Ligasa/metabolismo , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Xenoinjertos , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Pronóstico , Transducción de Señal , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Tirosina-ARNt Ligasa/biosíntesis , Tirosina-ARNt Ligasa/genética , Regulación hacia Arriba
6.
J Cancer Res Clin Oncol ; 146(2): 367-379, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31953613

RESUMEN

BACKGROUND: Long non-coding RNAs (lncRNAs) play crucial roles in the regulation and treatment of multiple myeloma (MM). The objective of this research was to study the functional mechanism of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in MM. METHODS: MALAT1, microRNA-1271-5p (miR-1271-5p), and SRY-Box 13 (SOX13) levels were examined by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability, apoptosis, and invasion were respectively assayed using 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT), flow cytometry, and transwell assay. Glycolysis was evaluated by glucose consumption, lactate production, ATP/ADP ratio, and the detection of related enzymes. Associated proteins were measured using Western blot. Target relation was verified via dual-luciferase reporter assay. Xenograft tumor assay was implemented to study the influence of MALAT1 on MM in vivo. RESULTS: The up-regulation of MALAT1 and the down-regulation of miR-1271-5p were found in MM serums and cells. MALAT1 knockdown suppressed cell viability, invasion, and glycolysis while expedited cell apoptosis in MM cells. MALAT1 directly targeted miR-1271-5p and miR-1271-5p depression reverted the effects of MALAT1 knockdown on MM cells. SOX13 was a target of miR-1271-5p and SOX13 overexpression weakened the effects of miR-1271-5p on MM. MALAT1 indirectly modulated SOX13 expression through targeting miR-1271-5p. MALAT1 down-regulation inhibited MM growth by miR-1271-5p/SOX13 axis in vivo. CONCLUSION: LncRNA MALAT1 expedited MM tumorigenesis, invasion, and glycolysis via miR-1271-5p/SOX13 axis. MALAT1 might contribute to the therapy of MM as a promising indicator.


Asunto(s)
Autoantígenos/metabolismo , MicroARNs/metabolismo , Mieloma Múltiple/metabolismo , ARN Largo no Codificante/metabolismo , Factores de Transcripción SOXD/metabolismo , Animales , Autoantígenos/genética , Carcinogénesis , Estudios de Casos y Controles , Línea Celular Tumoral , Glucólisis , Xenoinjertos , Humanos , Ratones , MicroARNs/genética , Mieloma Múltiple/sangre , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Invasividad Neoplásica , ARN Largo no Codificante/genética , Factores de Transcripción SOXD/genética
7.
Nat Commun ; 11(1): 573, 2020 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-31996677

RESUMEN

Hypoxia in solid tumors is thought to be an important factor in resistance to therapy, but the extreme microscopic heterogeneity of the partial pressures of oxygen (pO2) between the capillaries makes it difficult to characterize the scope of this phenomenon without invasive sampling of oxygen distributions throughout the tissue. Here we develop a non-invasive method to track spatial oxygen distributions in tumors during fractionated radiotherapy, using oxygen-dependent quenching of phosphorescence, oxygen probe Oxyphor PtG4 and the radiotherapy-induced Cherenkov light to excite and image the phosphorescence lifetimes within the tissue. Mice bearing MDA-MB-231 breast cancer and FaDu head neck cancer xenografts show different pO2 responses during each of the 5 fractions (5 Gy per fraction), delivered from a clinical linear accelerator. This study demonstrates subsurface in vivo mapping of tumor pO2 distributions with submillimeter spatial resolution, thus providing a methodology to track response of tumors to fractionated radiotherapy.


Asunto(s)
Fraccionamiento de la Dosis de Radiación , Procesamiento de Imagen Asistida por Computador/métodos , Oxígeno/química , Radioterapia/métodos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Ingeniería Biomédica/métodos , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/radioterapia , Línea Celular Tumoral , Femenino , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/radioterapia , Xenoinjertos , Humanos , Hipoxia , Metaloporfirinas , Ratones , Presión Parcial , Aceleradores de Partículas
8.
Adv Exp Med Biol ; 1232: 375-381, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31893434

RESUMEN

The value of optical redox imaging (ORI) of cells/tissues based on the intrinsic fluorescences of NADH (nicotinamide adenine dinucleotide) and oxidized flavoproteins (containing flavin adenine dinucleotide, i.e., FAD) has been demonstrated for potential biomedical applications including diagnosis, prognosis, and determining treatment response. However, the Chance redox scanner (a 3D cryogenic tissue imager) is limited by spatial resolution (~50 µm), and tissue ORI using fluorescence microscopy (single or multi-photon) is limited by the light penetration depth. Furthermore, viable or snap-frozen tissues are usually required. In this project, we aimed to study whether ORI may be achieved for unstained fixed tissue using a state-of-the-art modern Serial Two-Photon (STP) Tomography scanner that can rapidly acquire multi-plane images at micron resolution. Tissue specimens of mouse muscle, liver, and tumor xenografts were harvested and fixed in 4% paraformaldehyde (PFA) for 24 h. Tissue blocks were scanned by STP Tomography under room temperature to acquire the autofluorescence signals (NADH channel: excitation 750 nm, blue emission filter; FAD channel: excitation 860 nm, green emission filter). We observed remarkable signals with significant intra-tissue heterogeneity in images of NADH, FAD and redox ratio (FAD/(NADH+FAD)), which are worthy of further investigation for extracting biological information.


Asunto(s)
Tecnología Biomédica , NAD , Imagen Óptica , Animales , Tecnología Biomédica/instrumentación , Tecnología Biomédica/métodos , Estudios de Factibilidad , Flavina-Adenina Dinucleótido , Xenoinjertos/diagnóstico por imagen , Ratones , Oxidación-Reducción , Fotones
9.
Anticancer Res ; 40(1): 169-176, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892565

RESUMEN

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


Asunto(s)
Receptores de Hialuranos/metabolismo , Células Madre Neoplásicas/metabolismo , Animales , Biomarcadores , Biomarcadores de Tumor , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Modelos Animales de Enfermedad , Citometría de Flujo , Fluorouracilo/farmacología , Xenoinjertos , Humanos , Receptores de Hialuranos/genética , Ratones
10.
Anticancer Res ; 40(1): 191-199, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892567

RESUMEN

AIM: To evaluate the feasibility of conducting studies of saliva circulating tumor DNA (ctDNA) as a biomarker of metastasis or recurrence in our orthotopic head and neck cancer (HNC) mouse model. MATERIALS AND METHODS: A mouse model of recurrence or metastasis after tongue cancer resection was developed. Blood and saliva were collected at baseline and at the establishment of recurrence or metastasis. Real-time polymerase chain reaction was performed to quantify human long interspersed element (hLINE) in samples to assess the amount of ctDNA. RESULTS: In our model, salivary hLINE increased as the cancer developed and decreased after surgery. Plasma hLINE was significantly elevated in mice with metastasis. The presence of tongue cancer recurrence in mice was more correlated with hLINE concentration in saliva than in plasma. CONCLUSION: In our orthotopic model, salivary ctDNA better reflected tumor development and recurrence than did plasma ctDNA.


Asunto(s)
Biomarcadores de Tumor , ADN Tumoral Circulante , Neoplasias de Cabeza y Cuello/metabolismo , Saliva/metabolismo , Animales , Apoptosis/genética , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Neoplasias de Cabeza y Cuello/patología , Xenoinjertos , Humanos , Elementos de Nucleótido Esparcido Largo , Ratones , Recurrencia
11.
Zhonghua Yi Xue Za Zhi ; 100(1): 51-56, 2020 Jan 07.
Artículo en Chino | MEDLINE | ID: mdl-31914559

RESUMEN

Objective: To explore the feasibility of dynamic-enhanced magnetic resonance imaging (DCE-MRI) and blood oxygen level-dependent MRI (BOLD-MRI) in assessing the hemodynamics and tumor aggressiveness during treatment. Methods: The colon cancer xenograft model was established in BALB/C nude mice with HCT116 cell line. Sixteen nude mice were randomly divided into treatment and control groups (aged 6 to 8 weeks, weighted 15 to 18 g, Certificate No. 11400700325797), which were treated with bevacizumab and saline by intraperitoneal injection on the 1st, 4th, 7th, 10th and 13th day. DCE-MRI and BOLD-MRI were performed before and on the 3th, 6th, 9th, 12th, and 15th day after treatment. The vascular maturity and microenvironment hypoxia were confirmed by pathology. Results: The tumor volume of treatment group was significantly smaller than that of control group after 15 days ((712±43) vs (1 051±112) mm(3),P<0.01).The measurements of K(trans) were (0.135±0.005),(0.147±0.006),(0.175±0.009),(0.161±0.006), (0.140±0.005),(0.116±0.008)/min (F=81.386, P<0.01); K(ep) were (0.788±0.030),(0.804±0.036),(0.983±0.059), (1.105±0.091),(0.840±0.047),(0.786±0.041)/min(F=45.901,P<0.01);Ve were (0.652±0.006), (0.559±0.026), (0.466±0.016), (0.286±0.027), (0.363±0.020), (0.246±0.033) (F=384.290, P<0.01) and R2* values were (24.813±0.961), (24.675±1.070), (21.425±1.371), (17.850±0.885), (24.613±0.640), (27.013±0.734)/s (F=89.323, P<0.01) showed different trends with time in the treatment group, and the differences were statistically significant. The K(trans) values and tumor vessel maturity index (VMI) were higher than baseline values during 3-12 d after treatment. CD31 positive staining rate and VMI had the strongest correlations with K(trans) values (r=0.854 and 0.795), followed by AUC(180) (r=0.750 and 0.808), Ve (r=0.744 and 0.712) and K(ep) values (r=0.729 and 0.758), all P<0.05. R2* value positively correlated with the positive staining rate of HIF-1α and fibronectin (r=0.810 and 0.816), all P<0.05. Conclusion: DCE-MRI and BOLD-MRI are adequate to observe the tumor perfusion and hypoxia during anti-vascular treatment, and the R2* value can predict the tumor metastatic potential during the process of vascular normalization.


Asunto(s)
Medios de Contraste , Imagen por Resonancia Magnética , Animales , Xenoinjertos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos
12.
Life Sci ; 243: 117323, 2020 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-31954160

RESUMEN

AIMS: Circular RNAs (circRNAs) have been emerged as novel regulators in multiple tumorigenesis, including melanoma. CircRNA_0084043 was recently demonstrated to be deregulated in human melanoma cells. Nevertheless, its role and mechanism are largely unrevealed in melanoma. MATERIALS AND METHODS: Expression of circ_0084043, miRNA (miR)-429 and tribbles homolog 2 (TRIB2) was detected using reverse transcription-quantitative PCR quantitative PCR (RT-qPCR) and western blotting. Cell proliferation, apoptosis, migration and invasion were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry and transwell assays, respectively. The activation of Wnt/ß-catenin pathway was evaluated by western blotting. The target binding among circ_0084043, miR-429 and TRIB2 was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation. In vivo, mice xenograft model was generated to investigate tumor growth. KEY FINDINGS: Expression of circ_0084043 and TRIB2 was upregulated in human melanoma tissues and cell lines. Both circ_0084043 knockdown and TRIB2 silencing could decrease cell proliferation, migration and invasion, but facilitate apoptosis in A375 and SK-MEL-28 cells. Furthermore, TRIB2 restoration partially abrogated the tumor-suppressive role of circ_0084043 knockdown in melanoma cells in vitro. Then, we verified that circ_0084043 positively and physically controlled TRIB2 expression through sponging miR-429. Besides, expression of ß-catenin, c-Myc and cyclinD1 was inhibited in A375 and SK-MEL-28 cells when circ_0084043 was knocked down, accompanied with increased miR-429 and decreased TRIB2. Notably, circ_0084043 downregulation impeded tumor growth of A375 cells in vivo. SIGNIFICANCE: Knockdown of circ_0084043 suppressed the malignant development of melanoma presumably through modulating miR429/TRIB2 axis and inactivating Wnt/ß-catenin signaling pathway.


Asunto(s)
Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Melanoma/patología , MicroARNs/metabolismo , Neoplasias Cutáneas/patología , Vía de Señalización Wnt , beta Catenina/metabolismo , Adulto , Anciano , Animales , Línea Celular Tumoral , Femenino , Xenoinjertos , Humanos , Masculino , Melanoma/metabolismo , Ratones Endogámicos BALB C , Persona de Mediana Edad , Neoplasias Cutáneas/metabolismo
13.
Food Chem Toxicol ; 135: 110991, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31765699

RESUMEN

The goal of this research was to study the selective pro-apoptotic effect of ligustilide on prostate-cancer-associated fibroblast in the tumor microenvironment and the related molecular mechanisms. The effects of ligustilide on cancer-associated fibroblasts (CAFs) and normal fibroblasts (NFs) isolated from the prostate were determined by MTT assay. Flow cytometry and cellular immunofluorescence were used to detect the effects of ligustilide on the cell cycle and apoptosis. Western blotting was used to detect the expression of apoptosis-related proteins after the action of ligustilide on CAFs. In the investigation, ligustilide had a selective pro-apoptotic effect on prostate-CAFs. After ligustilide treatment, the proportion of CAFs in the G2-M phase of the cell cycle increased, and the expression of apoptosis-related proteins (p-P53, Bcl-2, Caspase9 and Cytochrome C) changed. Ligustilide blocks the CAF cell cycle and induces the apoptosis of CAFs.


Asunto(s)
4-Butirolactona/análogos & derivados , Apoptosis/efectos de los fármacos , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Neoplasias de la Próstata/patología , Receptor Toll-Like 4/metabolismo , 4-Butirolactona/farmacología , Animales , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Receptor Toll-Like 4/genética , Microambiente Tumoral
14.
Gynecol Oncol ; 156(1): 211-221, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31776040

RESUMEN

OBJECTIVE: Cyclin-dependent kinase 7 (CDK7) engages tumor growth by acting as a direct link between the regulation of transcription and the cell cycle. Here, we investigated the clinical significance of CDK7 expression and its potential as a therapeutic target in epithelial ovarian cancer (EOC). METHODS: CDK7 expression was examined in 436 ovarian tissues including normal to metastatic ovarian tumors using immunohistochemistry, and its clinical implications were analyzed. Furthermore, we performed in vitro and in vivo experiments using CDK7 siRNA or a covalent CDK7 inhibitor (THZ1) to elucidate the effect of CDK7 inhibition on tumorigenesis in EOC cells. RESULTS: The patient incidence of high CDK7 expression (CDK7High) gradually increased from normal ovarian epithelium to EOC (P < 0.001). Moreover, CDK7High was associated with an advanced stage and high-grade histology (P = 0.035 and P = 0.011, respectively) in EOC patients and had an independent prognostic significance in EOC recurrence (P = 0.034). CDK7 inhibition with siRNA or THZ1 decreased cell proliferation and migration, and increased apoptosis in EOC cells, and this anti-cancer mechanism is caused by G0/G1 cell cycle arrest. In in vivo therapeutic experiments using cell-line xenograft and PDX models, CDK7 inhibition significantly decreased the tumor weight, which was mediated by cell proliferation and apoptosis. CONCLUSION: Mechanistic interrogation of CDK7 revealed that it is significantly associated with an aggressive phenotype of EOC, and it has independent prognostic power for EOC recurrence. Furthermore, CDK7 may be a potential therapeutic target for patients with EOC, whether platinum sensitive or resistant.


Asunto(s)
Carcinoma Epitelial de Ovario/enzimología , Quinasas Ciclina-Dependientes/biosíntesis , Neoplasias Ováricas/enzimología , Animales , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/biosíntesis , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Femenino , Xenoinjertos , Humanos , Inmunohistoquímica , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Recurrencia Local de Neoplasia/enzimología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Fenilendiaminas/farmacología , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología
15.
J Endod ; 46(1): 57-64.e1, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31759677

RESUMEN

INTRODUCTION: This study aims to develop and characterize the regenerative potential of an atelopeptidized treated dentin matrix xenograft using in vitro and in vivo models. METHODS: Freshly extracted bovine dentin was pulverized into 250- to 500-µm particles and demineralized with 17% EDTA for 1, 7, and 13 days. The samples were atelopeptidized with pepsin. The degree of demineralization and the effect of atelopeptidization were assessed using field emission scanning electron microscopy combined with energy-dispersive X-ray spectroscopy and Fourier transform infrared spectroscopy, respectively. The expression of dentin matrix acidic phosphoprotein 1, dentin sialophosphoprotein, and osteopontin was evaluated in dental pulp stem cells using quantitative real-time polymerase chain reaction. The samples were then implanted intramuscularly in rats for 30 days, and the inflammatory cells were quantified histologically. RESULTS: Field emission scanning electron microscopy combined with energy-dispersive X-ray spectroscopy revealed an exposed tubular structure of dentin after 1 and 7 days of demineralization. Fourier transform infrared spectroscopy confirmed the absence of amide peaks at 1260 to 1640/cm after atelopeptidization. The dental pulp stem cell expression of dentin matrix acidic phosphoprotein 1 and dentin sialophosphoprotein increased in all compared with the untreated control group (P < .05). The maximum expression rates were observed for the 1-day demineralized and atelopeptidized group. The 1-day demineralized group elicited the highest inflammatory response compared with the 7- or 13-day demineralized groups (P < .001). Atelopeptidization significantly decreased the inflammatory response only in the 1-day demineralized dentin group (P < .05). CONCLUSIONS: Atelopeptidization of 1-day demineralized dentin xenograft preserved the collagen structure, minimized the immune reaction, and provided sufficient regenerative potential.


Asunto(s)
Pulpa Dental , Dentina , Xenoinjertos , Ingeniería de Tejidos , Animales , Bovinos , Dentina/trasplante , Microscopía Electrónica de Rastreo , Péptidos , Ratas
16.
Gynecol Oncol ; 156(1): 251-259, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31767187

RESUMEN

The majority of endometrial cancers are detected early with a favourable prognosis. However, for patients with advanced disease, chemotherapy response rates and overall survival remains poor. The endometrial cancer population is typically elderly with multiple co-morbidities and aggressive cytotoxic therapy may be hazardous. Therefore, there is an urgent need to define optimal treatment strategies for advanced and recurrent disease and personalise therapy based on individual tumour and patient characteristics. Three-dimensional (3D) models that preserve the tumour microenvironment and tumour-stromal interactions are increasingly important for translational research with the advent of immunotherapy and molecularly targeted agents. 3D patient-relevant pre-clinical models in endometrial cancer include spheroids, patient-derived organoids, microfluidic systems, patient-derived xenografts and patient-derived explants. Here we present a review of available 3D modelling systems in endometrial cancers, highlighting their current use, advantages, disadvantages and applications to translational research with a focus on the power of the patient-derived explant platform.


Asunto(s)
Técnicas de Cultivo de Célula/métodos , Neoplasias Endometriales/patología , Animales , Carcinoma Endometrioide/tratamiento farmacológico , Carcinoma Endometrioide/patología , Ensayos de Selección de Medicamentos Antitumorales/métodos , Neoplasias Endometriales/tratamiento farmacológico , Femenino , Xenoinjertos , Humanos , Trasplante de Neoplasias/métodos , Organoides/patología , Esferoides Celulares/patología , Investigación en Medicina Traslacional/métodos
17.
Clin Oral Investig ; 24(2): 1013-1023, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31286260

RESUMEN

OBJECTIVES: To assess dimensional changes following alveolar ridge preservation using bovine-derived xenograft with 10% collagen and collagen membrane compared to ridge preservation by means of bovine-derived xenograft particles and collagen membrane or spontaneous healing in posterior sites. MATERIALS AND METHODS: Forty subjects with 40 posterior teeth or roots candidate to extraction and presenting integrity of alveolar bone walls were randomly allocated into three groups. Patients of test group were treated by ridge preservation technique using bovine-derived xenograft with 10% collagen and collagen membrane; patients of control group 1 were treated by means of bovine-derived xenograft particles and collagen membrane while in patients of control group 2, no grafting was performed. Changes in vertical and horizontal bone dimensions were compared at baseline and after 6-month observation time. RESULTS: Statistically significant differences between baseline and 6 month were observed in all groups in terms of vertical and horizontal bone resorption (p < 0.001), except for vertical resorption in control group 2. After 6-month intergroup comparisons showed not statistically significant changes between test and control groups in terms of alveolar bone changes (p > 0.05). CONCLUSIONS: Within the limits of this study, the sites grafted using bovine-derived xenograft with 10% collagen in combination with a collagen membrane showed no statistical differences in terms of vertical and horizontal bone resorption compared to control groups. CLINICAL RELEVANCE: Ridge preservation in posterior area failed to show clinically relevant benefits in sites presenting integrity of alveolar bone walls and adequate buccal bone wall thickness.


Asunto(s)
Pérdida de Hueso Alveolar , Proceso Alveolar , Aumento de la Cresta Alveolar , Animales , Bovinos , Colágeno , Xenoinjertos , Humanos , Extracción Dental , Alveolo Dental
18.
Int J Cancer ; 146(5): 1383-1395, 2020 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-31286509

RESUMEN

Hepatocellular carcinoma (HCC) is an aggressive malignancy with increasing mortality in China. Angiogenesis is crucial for tumor formation, development and metastasis in HCC. Previous studies indicated that high expression levels of elongation factor 2 kinase (eEF2K), a protein kinase that negatively regulates the elongation stage of translation, were associated with poor prognosis of HCC. Here, we show that pharmacological inhibition or knockdown of eEF2K in highly metastatic liver cancer cells inhibits their colony forming and migratory capacities, as well as reducing their invasiveness. Importantly, knocking down eEF2K by lentiviral directed shRNA prevented tumor growth and angiogenesis of HCC in mice. Silencing of eEF2K in endothelial cells (HUVECs) led to a reduction in vascularization, evidenced by a decrease in capillary-like structures in the matrigel. Notably, knocking down eEF2K reduced the expression of angiogenesis-related growth factors in liver cancer cells and the expression of growth factor receptors on HUVECs, and thus restricted signaling crosstalk that promotes angiogenesis between HCC cells and endothelial cells. We also showed that silencing of eEF2K effectively reduced protein levels of SP1/KLF5 transcription factors and hence decreased the levels of bound SP1/KLF5 to the VEGF promoter, resulted in a decrease in VEGF mRNA expression. Knocking down eEF2K also led to a striking decrease in the phosphorylation of PI3K/Akt and STAT3, indicating inactivation of these tumorigenic pathways. Taken together, our data suggest that eEF2K contributes to angiogenesis and tumor progression in HCC via SP1/KLF5-mediated VEGF expression, as well as the subsequent stimulation of PI3K/Akt and STAT3 signaling.


Asunto(s)
Carcinoma Hepatocelular/irrigación sanguínea , Quinasa del Factor 2 de Elongación/metabolismo , Neoplasias Hepáticas/irrigación sanguínea , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Células Hep G2 , Xenoinjertos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Transducción de Señal
19.
Int J Cancer ; 146(5): 1369-1382, 2020 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-31276604

RESUMEN

The prognosis of patients with progressive prostate cancers that are hormone refractory and/or have bone metastasis is poor. Multiple therapeutic targets to improve prostate cancer patient survival have been investigated, including orphan GPCRs. In our study, we identified G Protein-Coupled Receptor Class C Group 5 Member A (GPRC5A) as a candidate therapeutic molecule using integrative gene expression analyses of registered data sets for prostate cancer cell lines. Kaplan-Meier analysis of TCGA data sets revealed that patients who have high GPRC5A expression had significantly shorter overall survival. PC3 prostate cancer cells with CRISPR/Cas9-mediated GPRC5A knockout exhibited significantly reduced cell proliferation both in vitro and in vivo. RNA-seq revealed that GPRC5A KO PC3 cells had dysregulated expression of cell cycle-related genes, leading to cell cycle arrest at the G2/M phase. Furthermore, the registered gene expression profile data set showed that the expression level of GPRC5A in original lesions of prostate cancer patients with bone metastasis was higher than that without bone metastasis. In fact, GPRC5A KO PC3 cells failed to establish bone metastasis in xenograft mice models. In addition, our clinical study revealed that GPRC5A expression levels in prostate cancer patient samples were significantly correlated with bone metastasis as well as the patient's Gleason score (GS). Combined assessment with the immunoreactivity of GPRC5A and GS displayed higher specificity for predicting the occurrence of bone metastasis. Together, our findings indicate that GPRC5A can be a possible therapeutic target and prognostic marker molecule for progressive prostate cancer.


Asunto(s)
Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Receptores Acoplados a Proteínas G/biosíntesis , Animales , Neoplasias Óseas/genética , Puntos de Control del Ciclo Celular/genética , Proliferación Celular/fisiología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Técnicas de Inactivación de Genes , Xenoinjertos , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células PC-3 , Fosforilación , Neoplasias de la Próstata/genética , Receptores Acoplados a Proteínas G/genética
20.
Bull Cancer ; 107(1): 30-40, 2020 Jan.
Artículo en Francés | MEDLINE | ID: mdl-31466696

RESUMEN

Primarily used in genetic studies of development, the zebrafish (Danio rerio) has rapidly emerged as a promising animal model of human cancer. Cancer cell transplantation in zebrafish constitutes a key platform for clinical research since it allows to study cellular and molecular events involved in various aspects of tumorigenesis and to evaluate the efficacy of therapeutic molecules in vivo. Applied to patient-derived cells, the xenotransplantation approach in zebrafish allows to define the most appropriate therapeutic strategies for specific alterations found in patients in the context of personalized medicine. This review discusses the zebrafish transplantation model for the study of cancer development and drug discovery.


Asunto(s)
Trasplante de Neoplasias , Neoplasias Experimentales/etiología , Medicina de Precisión/métodos , Investigación en Medicina Traslacional/métodos , Pez Cebra , Inmunidad Adaptativa , Animales , Animales Modificados Genéticamente , Transformación Celular Neoplásica , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Descubrimiento de Drogas , Genes Relacionados con las Neoplasias , Xenoinjertos , Humanos , Inmunosupresión/métodos , Neoplasias Experimentales/genética , Oncogenes , Ensayos Antitumor por Modelo de Xenoinjerto , Pez Cebra/embriología , Pez Cebra/genética , Pez Cebra/inmunología
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