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Braz. dent. j ; 32(4): 74-82, July-Aug. 2021. tab, graf
Article in English | LILACS, BBO | ID: biblio-1345513


Abstract The Inhibitor of Growth (ING) gene family is a group of tumor suppressor genes that play important roles in cell cycle control, senescence, DNA repair, cell proliferation, and apoptosis. However, inactivation and downregulation of these proteins have been related in some neoplasms. The present study aimed to evaluate the immunohistochemical profiles of ING3 and ING4 proteins in a series of benign epithelial odontogenic lesions. Methods: The sample comprised of 20 odontogenic keratocysts (OKC), 20 ameloblastomas (AM), and 15 adenomatoid odontogenic tumors (AOT) specimens. Nuclear and cytoplasmic immunolabeling of ING3 and ING4 were semi-quantitatively evaluated in epithelial cells of the odontogenic lesions, according to the percentage of immunolabelled cells in each case. Descriptive and statistics analysis were computed, and the p-value was set at 0.05. Results: No statistically significant differences were found in cytoplasmic and nuclear ING3 immunolabeling among the studied lesions. In contrast, AOTs presented higher cytoplasmic and nuclear ING4 labeling compared to AMs (cytoplasmic p-value = 0.01; nuclear p-value < 0.001) and OKCs (nuclear p-value = 0.007). Conclusion: ING3 and ING4 protein downregulation may play an important role in the initiation and progression of more aggressive odontogenic lesions, such as AMs and OKCs.

Resumo Objetivos: A família dos Genes Inibidores de Crescimento (ING) é um grupo de genes supressores tumorais que desempenham papéis importantes no controle do ciclo celular, na senescência, no reparo do DNA, na proliferação celular e na apoptose. No entanto, a inativação e a regulação negativa dessas proteínas têm sido relacionadas em algumas neoplasias. O objetivo do presente estudo foi avaliar o perfil imuno-histoquímico das proteínas ING3 e ING4 em uma série de lesões odontogênicas epiteliais benignas. Métodos: A amostra foi composta por espécimes de 20 ceratocistos odontogênicos (CO), 20 ameloblastomas (AM) e 15 tumores odontogênicos adenomatoides (TOA). A imunoexpressão nuclear e citoplasmática de ING3 e ING4 foram avaliadas semi-quantitativamente nas células epiteliais das lesões odontogênicas, de acordo com a porcentagem de células imunomarcadas em cada caso. As análises descritivas e estatísticas foram computadas, e o valor de p estabelecido foi de 0,05. Resultados: Não foram encontradas diferenças estatisticamente significativas na imunoexpressão citoplasmática e nuclear de ING3 entre as lesões estudadas. Em contrapartida, os TOAs apresentaram maior marcação citoplasmática e nuclear de ING4 em comparação aos AMs (valor de p citoplasmático=0,01; valor de p nuclear <0,001) e COs (valor nuclear de p=0,007). Conclusão: A regulação negativa das proteínas ING3 e ING4 pode desempenhar um papel importante na iniciação e na progressão de lesões odontogênicas mais agressivas, como AMs e COs.

Humans , Ameloblastoma , Odontogenic Cysts , Odontogenic Tumors , Homeodomain Proteins , Cell Cycle Proteins , Tumor Suppressor Proteins , Cell Proliferation
Int. j. morphol ; 38(2): 247-251, abr. 2020. tab, graf
Article in English | LILACS | ID: biblio-1056430


Nine tumor and various potential biomarkers were measured and combined the information to diagnose disease, all patients accepted fiber bronchoscopy brush liquid based cytologyand histopathology examination in order to reliably detect lung cancer. The samples from 314 Chinese lung cancer patients were obtained and CK5/6, P63, P40, CK7, TTF-1, NapsinA CD56, Syn and CgA were measured with the immunohistochemical SP method and analyzed correlation of the expression of these markers with pathological and clinical features of squamous cell carcinoma, adenocarcinoma, and small cell lung carcinoma. Squamous cell carcinoma, adenocarcinoma and small cell carcinoma were 61 cases, 114 cases and 139 cases,CK5/6 and P63 expression were more frequent in squamous cell carcinoma, with sensitivity and specificity of 77.05 % and 96.44 %, 83.61 % and 88.93 %,and compared with adenocarcinoma and small cell carcinoma difference was statistically significant (P<0.05), The incidences of a positive P40 expression were 100 % in squamous cell carcinoma, with specificity of 98.81 %.CK7, TTF-1 and NapsinA expression were more frequent in adenocarcinoma, with sensitivity and specificity of 85.09 % and 78.69 %, 79.82 % and 93.44 %, 56.14 % and 95.08 %, and compared with squamous cell carcinoma and small cell carcinoma difference was statistically significant (P<0.05). TTF-1, Syn, CgA and CD56 expression were more frequent in adenocarcinoma, with sensitivity and specificity of 86.33 % and 93.44 %, 89.21 % and 98.36 %, 74.10 % and 100 %, 96.40 % and 96.72 %. The combined detection of CK5/6, P63 and P40 were more useful and specific in differentiating squamous cell carcinoma. CK7, TTF-1 and NapsinA were more useful and specific in differentiating lung adenocarcinoma. The impaired CD56, TTF-1, Syn and CgA reflects the progression of small cell lung cancer.

Se midieron tumores y utilizaron nueve biomarcadores potenciales y se analizó la información para diagnosticar la enfermedad. A todos los pacientes se les realizó citología en líquido con broncoscopía de fibra y examen histopatológico para detectar de manera confiable el cáncer pulmonar. Se obtuvieron muestras de 314 pacientes chinos con cáncer de pulmón y CK5 / 6, P63, P40, CK7, TTF-1, Napsina A, CD56, Syn y CgA se midieron a través de histoquímica SP y analizaron la correlación de la expresión de estos marcadores con características patológicas y clínicas de carcinoma de células escamosas, adenocarcinoma y carcinoma de células pequeñas en el cáncer de pulmón. El carcinoma de células escamosas, el adenocarcinoma y el carcinoma de células pequeñas fueron 61 casos, 114 casos y 139 casos, respectivamente, la expresión de CK5 / 6 y P63 fueron más frecuentes en el carcinoma de células escamosas, con una sensibilidad y especificidad del 77,05 % y 96,44 %, 83,61 % y 88,93 %, y en comparación con el adenocarcinoma y el carcinoma de células pequeñas, la diferencia fue estadísticamente significativa (P <0,05). La incidencia de ap la expresión positiva P40 fue del 100 % en el carcinoma de células escamosas, con una especificidad del 98,81 %. La expresión de CK7, TTF-1 y NapsinA fueron más frecuentes en el adenocarcinoma, con una sensibilidad y especificidad del 85,09 % y 78,69 %, 79,82 % y 93,44 %, 56,14 % y 95,08 %, y en comparación con el carcinoma de células escamosas y la diferencia de carcinoma de células pequeñas fue estadísticamente significativa (P <0,05) .TTF-1, Syn, CgA y la expresión de CD56 fueron más frecuentes en adenocarcinoma, con sensibilidad y especificidad de 86.33 % y 93.44 %, 89.21 % y 98.36 %, 74.10 % y 100 %, 96.40 % y 96.72 %. La detección combinada de CK5 / 6, P63 y P40 fue más útil y específica en la diferenciación del carcinoma de células escamosas. CK7, TTF-1 y NapsinA fueron más útiles y específicos para diferenciar el adenocarcinoma de pulmón. El deterioro de CD56, TTF-1, Syn y CgA refleja la progresión del cáncer de pulmón de células pequeñas.

Humans , Carcinoma/metabolism , Carcinoma/pathology , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Peptide Fragments/metabolism , Transcription Factors/metabolism , Immunohistochemistry , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Biomarkers, Tumor/metabolism , Aspartic Acid Endopeptidases/metabolism , Sensitivity and Specificity , Carcinoma, Small Cell/metabolism , Carcinoma, Small Cell/pathology , CD56 Antigen/metabolism , Tumor Suppressor Proteins/metabolism , Keratins, Type II/metabolism , Keratin-7/metabolism , Thyroid Nuclear Factor 1/metabolism
Int. j. med. surg. sci. (Print) ; 7(1): 69-77, mar. 2020. tab, graf
Article in English | LILACS | ID: biblio-1179284


According to data from studies, antioxidant herbal compounds are, likely to have a useful role in reducing the harmful effects of environmental pollutants and toxic chemicals that most people are exposed to. Cadmium is one of the toxic elements that accumulate in many organs, especially in kidneys. The aim of this study was to investigate the effect of crocin on the expression of PKHD1 and KLLN genes in cadmium-treated rats.In this experimental study, 40 adults male Wistar rats (200-250 g) were randomly divided into the following groups: control group received normal saline, cadmium group (15mg/kg), crocin group (20mg/kg) and cadmium group daily fed with crocin at a dose of 20 mg/kg.After eight weeks of treatment, rats were dissected, and kidney tissues were removed for evaluation of PKHD1 and KLLN gene expression by real time method. The data were analyzed using one-way ANOVA and significant difference between groups was P<0.05.Our results showed an increase in PKHD1 gene expression and a decrease in KLLN gene expression in kidney tissue in the cadmium group compared to the control group (P <0.001).Also, a significant decrease in PKHD1 gene expression (P <0.001) and an increase in KLLN gene expression P <0.05) were observed in the tissues of all cadmium-treated rats compared to cadmium.Crocin consumption can have a protective effect against the impaired expression of PKHD1 and KLLN cadmium-induced apoptotic pathway.

Diversos estudios sugieren que compuestos antioxidantes de hierbas tienen un papel útil en la reducción de los efectos nocivos de los contaminantes ambientales y los químicos tóxicos a los que está expuesta la mayoría de las personas. El cadmio es uno de los elementos tóxicos que se acumulan en muchos órganos, especialmente en los riñones. El objetivo de este estudio fue investigar el efecto de la crocina en la expresión de los genes PKHD1 y KLLN en ratas tratadas con cadmio.En este estudio experimental, 40 ratas Wistar macho adultas (200-250 g) se dividieron aleatoriamente en los siguientes grupos: el grupo de control recibió solución salina normal, el grupo de cadmio (15 mg / kg), el grupo de crocina (20 mg / kg) y el grupo de cadmio alimentado diariamente con crocina a una dosis de 20 mg / kg.Después de ocho semanas de tratamiento, se disecaron las ratas y se extrajeron los tejidos renales para evaluar la expresión de los genes PKHD1 y KLLN mediante un método en tiempo real. Los datos se analizaron mediante ANOVA de una vía y la diferencia significativa entre los grupos fue P <0,05.Nuestros resultados mostraron un aumento en la expresión del gen PKHD1 y una disminución en la expresión del gen KLLN en el tejido renal en el grupo de cadmio en comparación con el grupo de control (P <0,001).Además, se observó una disminución significativa en la expresión del gen PKHD1 (P <0,001) y un aumento en la expresión del gen KLLN P <0,05) en los tejidos de todas las ratas tratadas con cadmio en comparación con el cadmio.El consumo de crocina puede tener un efecto protector contra la expresión alterada de la vía apoptótica inducida por cadmio PKHD1 y KLLN.

Animals , Rats , Cadmium/therapeutic use , Carotenoids/pharmacology , Receptors, Cell Surface/genetics , Tumor Suppressor Proteins/genetics , Rats, Wistar , Kidney Neoplasms/drug therapy
Article in English | WPRIM | ID: wpr-880305


BACKGROUND@#Particulate matter (PM) < 2.5 μm (PM@*METHODS@#We obtained DNA methylation and exercise data of 496 participants (aged between 30 and 70 years) from the Taiwan Biobank (TWB) database. We also extracted PM@*RESULTS@#DLEC1 methylation and PM@*CONCLUSIONS@#We found significant positive associations between PM

Adult , Aged , Air Pollutants/adverse effects , DNA Methylation/drug effects , Environmental Exposure/adverse effects , Exercise , Female , Humans , Male , Middle Aged , Particulate Matter/adverse effects , Taiwan , Tumor Suppressor Proteins/metabolism
Journal of Experimental Hematology ; (6): 1939-1945, 2020.
Article in Chinese | WPRIM | ID: wpr-879996


OBJECTIVE@#To investigate the effect of lncRNA-CASC2 (CASC2) /miR-155-5p/APC axis to the progression of non-Hodgikn lymphoma (NHL).@*METHODS@#The expression level of CASC2 and miR-155-5p in NHL cell lines were examined by qRT-PCR. Dual-luciferase reporter gene assay was used to verify the relationship between miR-155-5p, CASC2 and APC. The effects of CASC/miR-155-5p/APC axis to the proliferation, invasion and apoptosis of NK-92 cells were detected by MTT, Transwell assay and flow cytometry assay, respectively.@*RESULTS@#CASC2 was downregulated in NHL cell lines. Overexpression of CASC2 could inhibit the proliferation and invasion of NK-92 cells, and promote its apoptosis. Dual-luciferase reporter gene assay confirmed that there was a targeting relationship between miR-155-5p, CASC2 and APC. The restoration experiments proved that knockdown of both miR-155-5p and CASC2 or APC could restore the inhibitory effect of miR-155-5p silencing to the biological behavior of NK-92 cells.@*CONCLUSION@#Overexpression of CASC2 suppresses the proliferation and invasion of NK-92 cells, promote the apoptosis of NK-92 cells via targeting miR-155-5p and upregulating APC expression.

Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Humans , Lymphoma, Non-Hodgkin/genetics , MicroRNAs/genetics , RNA, Long Noncoding/genetics , Tumor Suppressor Proteins/genetics
Braz. oral res. (Online) ; 34: e052, 2020. tab, graf
Article in English | LILACS, BBO | ID: biblio-1132707


Abstract The purpose of this study was to analyze the differential expression of DEC1 in oral normal mucosa (NM), oral leukoplakia (OLK) and oral squamous cell carcinoma (OSCC). Surgically excised specimens from patients with OLK (n = 47), OSCC (n = 30) and oral normal mucosa (n=11) were immunostained for DEC1. The expression of DEC1 protein was evaluated, and its association with the clinicopathological features was analyzed. The expression of DEC1 in NM, OLK and OSCC tissues increased in turn, and significant differences were observed among the groups (P < 0.0001). In terms of the association between DEC1 expression and epithelial dysplasia, DEC1 expression was lower in hyperkeratosis without dysplasia (H-OLK) than in OLK with moderate to severe dysplasia (S-OLK), and these differences were significant (p < 0.05). The expression of DEC1 in OSCC with OLK was significantly higher than that in OSCC without OLK (p < 0.01). Therefore, DEC1 could be a potential biomarker of malignant transformation in the carcinogenesis of OSCC, which may provide a new research direction for the transformation of oral potentially malignant disorders (OPMDs) into OSCC.

Humans , Male , Female , Adult , Aged , Aged, 80 and over , Leukoplakia, Oral/pathology , Mouth Neoplasms/pathology , Carcinoma, Squamous Cell/pathology , Tumor Suppressor Proteins/analysis , Reference Values , Immunohistochemistry , Biomarkers, Tumor/analysis , Cell Transformation, Neoplastic/pathology , Reproducibility of Results , Risk Factors , Analysis of Variance , Age Factors , Statistics, Nonparametric , Middle Aged
Rev. Hosp. Ital. B. Aires (2004) ; 39(4): 146-148, dic. 2019. ilus
Article in Spanish | LILACS | ID: biblio-1099838


Los anticuerpos monoclonales que inhiben los puntos de control PD-1 y CTLA-4 se usan actualmente en el tratamiento del melanoma y cáncer metastásico de pulmón de células no pequeñas, entre otros. Se refiere el caso de una paciente con cáncer de pulmón en tratamiento con pembrolizumab. La paciente se presentó con edema facial y parálisis facial periférica. En el laboratorio se observó la hormona tirotrofina (TSH) elevada y se llegó al diagnóstico de hipotiroidismo por pembrolizumab. Inició tratamiento con levotiroxina con mejoría clínica. Se presenta este caso por el importante papel del dermatólogo en el manejo multidisciplinario del paciente oncológico. (AU)

Monoclonal antibodies that inhibit PD-1 and CTLA-4 control points are currently used in the treatment of melanoma and metastatic non-small cell lung cancer, among others. The case of a patient, with lung cancer being treated with Pembrolizumab. The patient was presented with facial edema and peripheral facial paralysis and in the laboratory the elevated hormone Tyrotrophin (TSH) was observed, the diagnosis of pembrolizumab hypothyroidism was reached. She started treatment with levothyroxine with clinical improvement. This case is presented by the important role of the dermatologist in the multidisciplinary management of the cancer patient. (AU)

Humans , Female , Middle Aged , M Phase Cell Cycle Checkpoints/drug effects , Immunotherapy/adverse effects , Antibodies, Monoclonal/adverse effects , Thyroxine/therapeutic use , Brain Neoplasms/complications , Brain Neoplasms/drug therapy , Thyrotropin/analysis , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/complications , Carcinoma, Non-Small-Cell Lung/drug therapy , Tumor Suppressor Proteins/drug effects , Dermatology , Facial Injuries , Facial Paralysis , CTLA-4 Antigen/drug effects , CTLA-4 Antigen/physiology , Programmed Cell Death 1 Receptor/drug effects , Programmed Cell Death 1 Receptor/physiology , Pemetrexed/administration & dosage , Melanoma/complications , Melanoma/drug therapy , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/therapeutic use , Neoplasm Metastasis/drug therapy
Article in English | WPRIM | ID: wpr-776615


OBJECTIVE@#To investigate the effects of Shengmai Injection (, SMI) on the proliferation, apoptosis and N-myc downstream-regulated gene 2 (NDRG2, a tumour suppressor gene) expression in varying densities of human hepatic stellate cells LX-2.@*METHODS@#LX-2 cells were cultured in vitro. Then, cells were plated in 96-well plates at an approximate density of 2.5×10 cells/mL and cultured for 48, 72, 96 or 120 h followed by the application of different concentrations of SMI (0.6, 1.2, 2.4, 4.8 or 6 μL/mL). Cell proliferation was measured after an additional 24 or 48 h using the 3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of SMI on different cell growth states (cultured for 48, 72, 96, or 120 h) were observed by light microscopy at 24 h after treatment. When the cells reached 80% conflfluence, apoptosis was detected by flflow cytometry after 24 h. Lastly, LX-2 cells were treated with different concentrations of SMI and extracted with protein lysis buffer. The levels of NDRG2 were measured by Western blot.@*RESULTS@#When the LX-2 cells grew for 48, 72, 96 and 120 h, 4.8 and 6 μL/mL of SMI significantly inhibited cell proliferation at 24 and 48 h after treatment (P<0.05). And 2.4 μL/mL of SMI also inhibited cell proliferation at 24 h after treatment when cell growth for 48 h (P<0.05) and at 48 h after treatment when cell growth for 72, 96 and 120 h (P<0.05). The NDRG2 expression level in the LX-2 cell was significantly increased when treated with SMI at concentrations of 1.2, 2.4, 4.8 or 6 μL/mL (P<0.05).@*CONCLUSION@#The inhibitory effects of SMI on the proliferation of LX-2 cells were related to not only concentration dependent but also cell density. In addition, SMI (2.4, 4.8 and 6 μL/mL) could accelerate apoptosis in LX-2 cells, and the mechanism might be associated with NDRG2 over-expression.

Apoptosis , Cell Proliferation , Cells, Cultured , Drugs, Chinese Herbal , Pharmacology , Hepatic Stellate Cells , Physiology , Humans , Injections , Liver Cirrhosis , Drug Therapy , Tumor Suppressor Proteins , Genetics
Acta Physiologica Sinica ; (6): 405-414, 2019.
Article in Chinese | WPRIM | ID: wpr-777173


The present study was aimed to investigate the expression relationship of Hippo signaling molecules and ovarian germline stem cell (OGSC) markers in the development schedule of OGSCs during ovarian aging in women and mice. The ovaries of 2-month-old mature (normal control) and 12-month-old (physiological ovarian aging) KM mice were sampled, and the ovarian cortex samples of young (postpuberty to 35 years old), middle age (36-50 years old) and menopausal period (51-60 years old) women were obtained with consent. The mice model of pathological ovarian aging was established by intraperitoneal injection of cyclophosphamide/busulfan (CY/BUS). HE staining was used to detect the changes of follicles at different stages, and the localization and expression changes of Hippo signaling molecules and OGSCs related factors (MVH/OCT4) were detected by immunohistochemistry and immunofluorescence staining. Western blot was used to detect the protein expression levels of the major molecules in the Hippo signaling pathway and OGSCs related factors. The results showed that there were not any normal follicles, but a few atresia follicles in the ovaries from physiological and pathological ovarian aging mice. Compared with the normal control mice, both the physiological and pathological ovarian aging mice showed decreased protein expression levels of the main Hippo signaling molecules (pYAP1) and MVH/OCT4; Whereas only the pathological ovarian aging mice showed increased ratio of pYAP1/YAP1. In comparison with the young women, the middle age and menopausal women showed looser structure of ovarian surface epithelium (OSE) and less ovarian cortical cells. The protein expression level of LATS2 in the OSE was the highest in young women, MST1 expression was the lowest in the menopausal period women, and the expression levels of YAP1 and pYAP1 were the highest in middle age women. Compared with the young women, the middle age and menopausal period women exhibited significantly decreased ratio of OSE pYAP1/YAP1, whereas there was no significant difference between them. The expression level of MVH protein in OSE from the young women was significantly higher than those of the middle age and menopausal period women. These results indicate that there is an expression relationship between the main molecules of Hippo signaling pathway and OGSCs related factors, which suggests that Hippo signaling pathway may regulate the expression levels of OGSCs related factors, thus participating in the process of physiological and pathological degeneration of ovarian.

Adaptor Proteins, Signal Transducing , Metabolism , Adult , Aging , Animals , Epithelium , Female , Humans , Mice , Middle Aged , Octamer Transcription Factor-3 , Metabolism , Oogonial Stem Cells , Metabolism , Ovarian Follicle , Ovary , Phosphoproteins , Metabolism , Protein-Serine-Threonine Kinases , Metabolism , Signal Transduction , Tumor Suppressor Proteins , Metabolism
Biol. Res ; 52: 18, 2019. graf
Article in English | LILACS | ID: biblio-1011420


BACKGROUND: MicroRNAs (miRNAs) have emerged as the critical modulators of the tumorigenesis and tumor progression. METHODS: The levels of miR-663 in ovarian cancer cell lines and clinical tissues were detected using qRT-PCR assays. The Transwell invasion and wound healing assay were conducted to assess the roles of miR-663 in the migration and invasion of ovarian cancer cell in vitro. Rescue assays were carried out to confirm the contribution of tumor suppressor candidate 2 (TUSC2) in the aggressiveness of cancer cell which was regulated by miR-663. RESULTS: The levels of miR-663 were up-regulated in ovarian cancer tissues in comparison with the corresponding normal tissues. Up-regulation of miR-663 increased the proliferation, colony formation, migration and invasion of ovarian cancer SKOV3 cell. Additional, over-expression of miR-663 increased the tumor growth of SKOV3 in xenograft model. Bioinformatics analysis and luciferase reporter assay identified that miR-663 decreased the level of TUSC2 via binding to the 3'-UTR of TUSC2 gene. Finally, the expression of TUSC2 was inversely associated with the level of miR-663 in ovarian carcinoma tissue and over-expression of TUSC2 inhibited the migration and invasion abilities of SKOV3 that was promoted by miR-663. CONCLUSION: Altogether, these results indicate that miR-663 acts as a potential tumor-promoting miRNA through targeting TUSC2 in ovarian cancer.

Humans , Female , Ovarian Neoplasms/pathology , Tumor Suppressor Proteins/metabolism , MicroRNAs/genetics , Transfection , Gene Expression Regulation, Neoplastic , Cell Movement , Reverse Transcriptase Polymerase Chain Reaction , Tumor Suppressor Proteins/genetics , Cell Line, Tumor , Cell Proliferation , Neoplasm Invasiveness/genetics
Article in Chinese | WPRIM | ID: wpr-772069


OBJECTIVE@#To investigate the effects of ribonucleotide reductase catalytic subunit M1 (RRM1) gene silencing on drug resistance of human breast cancer cell line MCF-7/R.@*METHODS@#We established a paclitaxel-resistant breast cancer MCF-7 cell line (MCF-7/R) by exposing the cells to high-concentration paclitaxel in a short time. Small interfering RNAs (siRNAs) targeting RRM1 were designed to silence RRM1 expression in human breast cancer MCF-7/R cells. MTT assay was used to detect the IC values and the sensitivity to paclitaxel in the cells with or without siRNA transfection. The changes in the proliferative activity of MCF7 and MCF-7/R cells following RRM1 gene silencing were evaluated using EdU assay. Flow cytometry was used to analyze the cell apoptosis and cell cycle changes. We assessed the effect of RRM1 gene silencing and paclitaxel on the tumor growth in a nude mouse model bearing subcutaneous xenografts with or without siRNA transfection.@*RESULTS@#We detected significantly higher expressions of RRM1 at both the mRNA and protein levels in the drug-resistant MCF- 7/R cells than in the parental MCF-7 cells ( < 0.01). Transfection with the specific siRNAs significantly reduced the expression of RRM1 in MCF-7/R cells ( < 0.05), which showed a significantly lower IC value of paclitaxel than the cells transfected with the negative control siRNA ( < 0.05). RRM1 silencing significantly inhibited the proliferation ( < 0.01) and enhanced the apoptosis-inducing effect of paclitaxel in MCF-7/R cells ( < 0.001); RRM1 silencing also resulted in obviously reduced Akt phosphorylation, suppressed Bcl-2 expression and promoted the expression of p53 protein in MCF-7/R cells. In the tumor-bearing nude mice, the volume of subcutaneously transplanted tumors was significantly smaller in MCF-7/R/siRNA+ PTX group than in the other groups ( < 0.001).@*CONCLUSIONS@#RRM1 gene silencing can reverse paclitaxel resistance in human breast cancer cell line MCF-7/R by promoting cell apoptosis.

Animals , Apoptosis , Breast Neoplasms , Drug Resistance, Neoplasm , Gene Silencing , Humans , MCF-7 Cells , Mice , Mice, Nude , Paclitaxel , RNA, Small Interfering , Ribonucleotide Reductases , Tumor Suppressor Proteins
Braz. j. otorhinolaryngol. (Impr.) ; 84(5): 599-607, Sept.-Oct. 2018. tab
Article in English | LILACS | ID: biblio-974364


Abstract Introduction: Adenoid hypertrophy is a condition that presents itself as the chronic enlargement of adenoid tissues; it is frequently observed in the pediatric population. The Ugrp2 gene, a member of the secretoglobin superfamily, encodes a low-molecular weight protein that functions in the differentiation of upper airway epithelial cells. However, little is known about the association of Ugrp2 genetic variations with adenoid hypertrophy. Objective: The aim of this study is to investigate the association of single nucleotide polymorphisms in the Ugrp2 gene with adenoid hypertrophy and its related phenotypes. Methods: A total of 219 children, comprising 114 patients suffering from adenoid hypertrophy and 105 healthy patients without adenoid hypertrophy, were enrolled in this study. Genotypes of the Ugrp2 gene were determined by DNA sequencing. Results: We identified four single nucleotide polymorphisms (IVS1-189G>A, IVS1-89T>G, c.201delC, and IVS2-15G>A) in the Ugrp2 gene. Our genotype analysis showed that the Ugrp2 (IVS1-89T>G) TG and (c.201delC) CdelC genotypes and their minor alleles were associated with a considerable increase in the risk of adenoid hypertrophy compared with the controls (p = 0.012, p = 0.009, p = 0.013, and p = 0.037, respectively). Furthermore, Ugrp2 (GTdelCG, GTdelCA) haplotypes were significantly associated with adenoid hypertrophy (four single nucleotide polymorphisms ordered from 5′ to 3′; p = 0.0001). Polymorfism-Polymorfism interaction analysis indicated a strong interaction between combined genotypes of the Ugrp2 gene contributing to adenoid hypertrophy, as well as an increased chance of its diagnosis (p < 0.0001). In addition, diplotypes carrying the mutant Ugrp2 (c.201delC) allele were strongly associated with an increased risk of adenoid hypertrophy with asthma and with allergies (p = 0.003 and p = 0.0007, respectively). Conclusion: Some single nucleotide polymorphisms and their combinations in the Ugrp2 gene are associated with an increased risk of developing adenoid hypertrophy. Therefore, we tried to underline the importance of genetic factors associated with adenoid hypertrophy and its related clinical phenotypes.

Resumo Introdução: A adenoide ou hipertrofia de tonsila faríngea é uma condição que se apresenta como o aumento crônico de tecidos linfoides na rinofaringe e é frequentemente observada na população pediátrica. O gene Ugrp2, um membro da superfamília da secretoglobina, codifica uma proteína de baixo peso molecular que funciona na diferenciação das células epiteliais das vias aéreas superiores. No entanto, pouco se sabe sobre a associação de variações genéticas do Ugrp2 com hipertrofia de tonsila faríngea. Objetivo: Investigar a associação de polimorfismos de nucleotídeos únicos no gene Ugrp2 com hipertrofia de tonsila faríngea e seus fenótipos relacionados. Método: Foram incluídos no estudo 219 crianças, 114 pacientes com hipertrofia de tonsila faríngea e 105 saudáveis. Os genótipos do gene Ugrp2 foram determinados por sequenciamento de DNA. Resultados: Identificamos quatro polimorfismos de nucleotídeo único (IVS1-189G>A, IVS1-89T>G, c.201delC, e IVS2-15G>A) no gene Ugrp2. Nossa análise genotípica mostrou que os genótipos Ugrp2 (IVS1-89T>G) TG e (c.201delC) CdelC e seus alelos menores foram associados a um aumento considerável no risco de HA em comparação com os controles (p = 0,012, p = 0,009, p = 0,013 e p = 0,037, respectivamente). Além disso, os haplótipos Ugrp2 (GTdelCG, GTdelCA) foram significativamente associados com hipertrofia de tonsila faríngea (quatro polimorfismos de nucleot' ordenados de 5' a 3'; p = 0,0001). A análise de interação polimorfismo-polimorfismo indicou uma forte interação entre genótipos combinados do gene Ugrp2 que contribuiu para hipertrofia de tonsila faríngea, bem como uma chance maior de seu diagnóstico (p < 0,0001). Além disso, os diplótipos que transportam o alelo mutante Ugrp2 (c.201delC) foram fortemente associados a um risco aumentado de hipertrofia de tonsila faríngea com asma e com alergias (p = 0,003 e p = 0,0007, respectivamente). Conclusão: Alguns polimorfismos de nucleotídeo único e suas combinações no gene Ugrp2 estão associados a um risco aumentado de desenvolver hipertrofia de tonsila faríngea. Portanto, tentamos enfatizar a importância dos fatores genéticos e fenótipos clínicos associados a essa hipertrofia.

Humans , Male , Female , Child, Preschool , Adenoids/pathology , Cytokines/genetics , Polymorphism, Single Nucleotide/genetics , Tumor Suppressor Proteins/genetics , Phenotype , Case-Control Studies , Genetic Predisposition to Disease , Gene Frequency , Genotype , Hypertrophy/genetics
Rev. méd. Chile ; 146(6): 762-769, jun. 2018. graf
Article in Spanish | LILACS | ID: biblio-961457


One of the main features of cancer is the high rate of cell proliferation and growth. To do this, cancer cells need to redirect their metabolism mainly towards anaerobic glycolysis and an increased mitochondrial glutamine energy metabolism. Sirtuins are cellular proteins with regulatory functions on metabolic pathways, genomic stability, apoptosis, longevity, inflammation, energy metabolism and oxidative stress. Sirtuins have emerged recently as a potential therapeutic option to treat several chronic diseases including cancer. This review summarizes the tumor suppressor function of Sirtuin 3 (SIRT3), highlighting its repressor effect on glycolytic metabolism, promoting mitochondrial metabolism and oxidative stress reduction. SIRT3 activation by exercise is particularly described since it may represent a potent tool for several types of cancer treatment.

Humans , Exercise/physiology , Sirtuin 3/physiology , Neoplasms/metabolism , Neoplasms/therapy , Reactive Oxygen Species/metabolism , Oxidative Stress/physiology , Tumor Suppressor Proteins/physiology , Exercise Therapy/methods , Mitochondria/metabolism
Rev. bras. ginecol. obstet ; 40(2): 79-85, Feb. 2018. tab, graf
Article in English | LILACS | ID: biblio-958959


Abstract Objective The current study evaluated the expression of WW domain-containing oxidoreductase (WWOX), its association with clinicopathological features and with p53, Ki-67 (cell proliferation) and CD31 (angiogenesis) expression in patients with invasive cervical squamous cell carcinoma (ICSCC). To the best of our knowledge, no other study has evaluated this association. Methods Women with IB stage-ICSCC (n = 20) and women with uterine leiomyoma (n = 20) were prospectively evaluated. Patients with ICSCC were submitted to type BC1 radical hysterectomy and pelvic lymphadenectomy. Patients in the control group underwent vaginal hysterectomy. Tissue samples were stained with hematoxylin and eosin for histological evaluation and protein expression was detected by immunohistochemistry studies. Results The WWOX expression was significantly lower in the tumor compared with the expression in thebenign cervix (p = 0.019). TheWWOXexpressionwas inversely associated with the CD31 expression in the tumor samples (p = 0.018). There was no association betweentheWWOXexpression with the p53 expression (p = 0.464)or the Ki-67expression (p = 0.360) in the samples of invasive carcinoma of the cervix. There was no association between the WWOX expression and tumor size (p = 0.156), grade of differentiation (p = 0.914), presence of lymphatic vascular invasion (p = 0.155), parametrium involvement (p = 0.421) or pelvic lymph node metastasis (p = 0.310) in ICSCC tissue samples. Conclusion The results suggested that WWOX may be involved in ICSCC carcinogenesis, and this marker was associated with tumor angiogenesis.

Resumo Objetivo O presente estudo avaliou a expressão do WWOX, sua associação com características clinicopatológicas e com a expressão do p53, ki-67 (proliferação celular) e CD31 (angiogênese) em pacientes com carcinoma invasivo de células escamosas do colo uterino, ou simplesmente câncer do colo uterino (CCE). Métodos Foram avaliadas prospectivamente pacientes com CCE no estágio IB (n = 20) e mulheres com mioma uterino, no grupo controle (n = 20). As pacientes com CCE foram submetidas à histerectomia radical e à linfadenectomia pélvica do tipo B-C1. As mulheres no grupo-controle foram submetidas à histerectomia vaginal. As amostras de tecido foramcoradas comhematoxilina e eosina para avaliação histológica e a expressão das proteínas foi detectada por imuno-histoquímico. Resultados A expressão do WWOX foi significativamente menor no tumor quando comparada com sua expressão no colo do útero benigno (p = 0,019). A expressão tumoral de CD31 foi inversamente associada à expressão de WWOX (p = 0,018). Sua expressão não foi associada à expressão tumoral de p53 e Ki-67 em pacientes com CCE (p = 0,464 e p = 0,360, respectivamente). Não houve associação entre a expressão de WWOX e o tamanho do tumor (p = 0,156), grau de diferenciação (p = 0,914), presença de invasão vascular linfática (p = 0,155), comprometimento do paramétrio (p = 0,421) ou metástase dos linfonodos pélvicos (p = 0,310) em pacientes com CCE. Conclusão Os resultados sugeriram que o WWOX pode estar envolvido na carcinogênese do CICECU e esse marcador foi associado à angiogênese tumoral.

Humans , Female , Adult , Aged , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Gene Expression Regulation, Neoplastic , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/pathology , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Proteins/genetics , Cell Proliferation , WW Domain-Containing Oxidoreductase/genetics , Neovascularization, Pathologic , Immunohistochemistry , Carcinoma, Squamous Cell/chemistry , Uterine Cervical Neoplasms/chemistry , Prospective Studies , Tumor Suppressor Protein p53/analysis , Tumor Suppressor Proteins/analysis , WW Domain-Containing Oxidoreductase/analysis , Middle Aged
Biol. Res ; 51: 58, 2018. graf
Article in English | LILACS | ID: biblio-1011402


BACKGROUND: Studies have demonstrated that transforming growth factor beta-1 (TGF-ß1) exhibits oncogenic activity in different types of cancer, including ovarian cancer (OC). However, its regulatory mechanism in OC and whether TGF-ß1 is involved in chemosensitivity regulation remains unclear. Thus, the aim of this study was to investigate the role of TGF-ß1 in OC. METHODS: The OC cell line SKOV3 was employed, and TGF-ß1 overexpression or knockdown vectors were constructed. The cell proliferation of SKOV3 was evaluated with the cell counting kit (CCK8) kit after treatment with different concentrations of cis-platinum. Western blot and protein immunoprecipitation were employed to detect changes in BRCA1 and Smad3 expression and their interactions. Tumor growth in nude mice was evaluated. RESULTS: The results showed that TGF-ß1 knockdown increased chemosensitivity by promoting BRCA1 expression and Smad3 phosphorylation. In vivo studies showed that TGF-ß1 knockdown significantly inhibited the growth of tumors, also by upregulating BRCA1 expression and Smad3 phosphorylation. CONCLUSION: Taken together, our results suggest that TGF-ß1 knockdown inhibits tumor growth and increases chemosensitivity by promotion of BRCA1/Smad3 signaling.

Humans , Animals , Male , Female , Ovarian Neoplasms/metabolism , Down-Regulation/physiology , Genes, BRCA1/physiology , Smad3 Protein/physiology , Transforming Growth Factor beta1/physiology , Ovarian Neoplasms/pathology , Ovarian Neoplasms/drug therapy , Immunohistochemistry , Cells, Cultured , Blotting, Western , Drug Resistance, Neoplasm/physiology , Tumor Suppressor Proteins/physiology , Cell Line, Tumor , Cell Proliferation , Smad3 Protein/analysis , Transforming Growth Factor beta1/analysis , Gene Knockdown Techniques , Real-Time Polymerase Chain Reaction , Mice, Inbred BALB C
Biol. Res ; 51: 22, 2018. graf
Article in English | LILACS | ID: biblio-950906


BACKGROUND: Our study aimed to investigate the roles of autophagy against high glucose induced response in retinal pigment epithelium (ARPE-19 cells). METHODS: The morphological changes and reactive oxygen species (ROS) generation in ARPE-19 cells under high glucose treatment were respectively detected using the transmission electron microscopy and flow cytometry. The expression levels of Parkin, PINK1, BNIP3L, LC3-I and LC3-II in ARPE-19 cells received high glucose treatment were measured by western blot after pretreatment of carbonyl cyanide m-chlorophenylhydrazone (CCCP), 3-methyladenine (3-MA), N-acetyl cysteine (NAC) or cyclosporin A (CsA) followed by high glucose treatment. RESULTS: ARPE-19 cells subjected to high glucose stress showed an obvious reduction in the LC3-I expression and significant increase in the number of autophagosomes, in the intracellular ROS level, and in the expression levels of Parkin, PINK1, BNIP3L and LC3-II (p < 0.05). Pretreatment with CCCP significantly reduced the LC3-I expression and increased the expression levels of Parkin, PINK1, BNIP3L and LC3-II (p < 0.05). ARPE-19 cells pretreated with CsA under high glucose stress showed markedly down-regulated expressions of Parkin, PINK1 and BNIP3L compared with the cells treated with high glucose (p < 0.05). Pretreatment of ARPE-19 cells with NAC or 3-MA under high glucose stress resulted in a marked reduction in the expression levels of PINK1, BNIP3L and LC3-II (p < 0.05). Meanwhile, the expression level of Parkin in the ARPE-19 cells pretreated with NAC under high glucose stress was comparable with that in the control cells. CONCLUSION: Autophagy might have protective roles against high glucose induced injury in ARPE19 cells via regulating PINK1/Parkin pathway and BNIP3L.

Humans , Protein Kinases/drug effects , Autophagy/drug effects , Proto-Oncogene Proteins/drug effects , Tumor Suppressor Proteins/drug effects , Ubiquitin-Protein Ligases/drug effects , Retinal Pigment Epithelium/drug effects , Glucose/pharmacology , Membrane Proteins/drug effects , Protein Kinases/metabolism , Autophagy/physiology , Signal Transduction/physiology , Cell Line , Proto-Oncogene Proteins/metabolism , Reactive Oxygen Species/metabolism , Tumor Suppressor Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Microscopy, Electron, Transmission , Retinal Pigment Epithelium/cytology , Flow Cytometry , Membrane Proteins/metabolism
Protein & Cell ; (12): 216-237, 2018.
Article in English | WPRIM | ID: wpr-756949


The tricarboxylic acid (TCA) cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance requirements. Despite early dogma that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, emerging evidence demonstrates that certain cancer cells, especially those with deregulated oncogene and tumor suppressor expression, rely heavily on the TCA cycle for energy production and macromolecule synthesis. As the field progresses, the importance of aberrant TCA cycle function in tumorigenesis and the potentials of applying small molecule inhibitors to perturb the enhanced cycle function for cancer treatment start to evolve. In this review, we summarize current knowledge about the fuels feeding the cycle, effects of oncogenes and tumor suppressors on fuel and cycle usage, common genetic alterations and deregulation of cycle enzymes, and potential therapeutic opportunities for targeting the TCA cycle in cancer cells. With the application of advanced technology and in vivo model organism studies, it is our hope that studies of this previously overlooked biochemical hub will provide fresh insights into cancer metabolism and tumorigenesis, subsequently revealing vulnerabilities for therapeutic interventions in various cancer types.

Animals , Citric Acid Cycle , Humans , Molecular Targeted Therapy , Methods , Neoplasms , Drug Therapy , Genetics , Metabolism , Pathology , Oncogenes , Genetics , Tumor Suppressor Proteins , Metabolism
Article in Chinese | WPRIM | ID: wpr-772450


OBJECTIVE@#To investigate the effect of large tumor suppressor homolog 2 (LATS2) gene overexpression on the proliferation and apoptosis of oral squamous cell carcinoma (OSCC).@*METHODS@#Lentivirous particles were transferred into SCC-25 cell to upregulate LATS2 gene expression. Cell proliferation was detected by CCK-8 assay. Apoptosis was detected through flow cytometry. The expression changes of Bax, Bcl-2, and LATS2 were analyzed by Western blot.@*RESULTS@#Gene transfection increased LATS2 expression. Compared with the control group and pEGFP-control group, SCC-25 cell proliferation in the pGFP-LATS2 group was inhibited, whereas the apoptosis ratio increased (P<0.05). Bcl-2 expression decreased, and Bax expression increased.@*CONCLUSIONS@#Overexpression of LATS2 could inhibit SCC-25 cell proliferation and induce apoptosis.

Apoptosis , Carcinoma, Squamous Cell , Genetics , Metabolism , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, Neoplastic , Humans , Mouth Neoplasms , Genetics , Metabolism , Protein-Serine-Threonine Kinases , Physiology , Tumor Suppressor Proteins , Physiology
Chinese Medical Journal ; (24): 939-944, 2018.
Article in English | WPRIM | ID: wpr-687005


<p><b>Background</b>Promoter methylation of MGMT and C13ORF18 has been confirmed as a potential biomarker for early diagnosis of cervical cancer. The aim of this study was to evaluate the performance of MGMT and C13ORF18 promoter methylation for triage of cytology screening samples and explore the potential mechanism.</p><p><b>Methods</b>Methylation-sensitive high-resolution melting was used to detect promoter methylation of MGMT and C13ORF18 in 124 cervical samples. High-risk human papillomavirus (HR-HPV) was detected by the Digene Hybrid Capture 2. Gene methylation frequencies in relation to cervical intraepithelial neoplasia (CIN) were analyzed. Frequencies were compared by Chi-square tests. The expression of gene biomarkers and methylation regulators was analyzed by immunohistochemical staining, real-time fluorescence quantitative polymerase chain reaction, and Western blot.</p><p><b>Results</b>For triage of low-grade squamous intraepithelial lesion (LSIL), gene methylation increased specificity from 4.0% of HR-HPV detection to 30.8% of MGMT (χ = 9.873, P = 0.002) and to 50.0% of C13ORF18 (χ = 21.814, P = 0.001). For triage of atypical squamous cells of undetermined significance, HR-HPV detection had higher positive predictive value of 54.8%. Either MGMT or C13ORF18 methylation combined with HR-HPV increased the negative predictive value to 100.0% (χ = 9.757, P = 0.002). There was no relationship between MGMT and C13ORF18 expression and DNA methylation (χ = 0.776, P = 0.379 and χ = 1.411, P = 0.235, respectively). MBD2 protein level in cervical cancer was relatively lower than normal cervical tissue (t = 4.11, P = 0.006).</p><p><b>Conclusions</b>HR-HPV detection is the cornerstone for triage setting of CIN. Promoter methylation of MGMT and C13ORF18 plays a limited role in triage of LSIL. Promoter methylation of both genes may not be the causes of gene silence.</p>

Adult , Cervical Intraepithelial Neoplasia , Genetics , Pathology , Chi-Square Distribution , DNA Methylation , Genetics , DNA Modification Methylases , Genetics , DNA Repair Enzymes , Genetics , Female , Humans , Middle Aged , Promoter Regions, Genetic , Genetics , Squamous Intraepithelial Lesions of the Cervix , Genetics , Pathology , Tumor Suppressor Proteins , Genetics , Uterine Cervical Neoplasms , Genetics , Pathology , Young Adult
Chinese Journal of Cancer ; (12): 2-2, 2018.
Article in English | WPRIM | ID: wpr-773012


BACKGROUND@#We previously showed that the expression of follistatin-like protein 1 (FSTL1) was significantly down-regulated in metastatic clear-cell renal cell carcinoma (ccRCC). In this study, we aimed to characterize the role of FSTL1 in the development of ccRCC.@*METHODS@#The effects of FSTL1 on cell activity and cell cycle were investigated in ccRCC cell lines with altered FSTL1 expression. Gene expression microarray assays were performed to identify the major signaling pathways affected by FSTL1 knockdown. The expression of FSTL1 in ccRCC and its effect on postoperative prognosis were estimated in a cohort with 89 patients.@*RESULTS@#FSTL1 knockdown promoted anchorage-independent growth, migration, invasion, and cell cycle of ccRCC cell lines, whereas FSTL1 overexpression attenuated cell migration. FSTL1 knockdown up-regulated nuclear factor-κB (NF-κB) and hypoxia-inducible factor (HIF) signaling pathways, increased epithelial-to-mesenchymal transition, up-regulated interleukin-6 expression, and promoted tumor necrosis factor-α-induced degradation of NF-κB inhibitor (IκBα) in ccRCC cell lines. FSTL1 immunostaining was selectively positive in epithelial cytoplasm in the loop of Henle, and positive rate of FSTL1 was significantly lower in ccRCC tissues than in adjacent renal tissues (P < 0.001). The multivariate Cox regression analysis showed that the intratumoral FSTL1 expression conferred a favorable independent prognosis with a hazard ratio of 0.325 (95% confidence interval 0.118-0.894). HIF-2α expression was negatively correlated with FSTL1 expression in ccRCC specimens (r = - 0.229, P = 0.044). Intratumoral expression of HIF-2α, rather than HIF-1α, significantly predicted an unfavorable prognosis in ccRCC (log-rank, P = 0.038).@*CONCLUSIONS@#FSTL1 plays a tumor suppression role possibly via repressing the NF-κB and HIF-2α signaling pathways. To increase FSTL1 expression might be a candidate therapeutic strategy for metastatic ccRCC.

Adult , Aged , Aged, 80 and over , Basic Helix-Loop-Helix Transcription Factors , Genetics , Carcinoma, Renal Cell , Genetics , Pathology , Cell Line, Tumor , Cell Movement , Genetics , Disease-Free Survival , Epithelial-Mesenchymal Transition , Genetics , Female , Follistatin-Related Proteins , Genetics , Gene Expression Regulation, Neoplastic , Genetics , Humans , Hypoxia-Inducible Factor 1, alpha Subunit , Genetics , Male , Middle Aged , NF-kappa B , Genetics , Neoplasm Metastasis , Signal Transduction , Genetics , Tumor Suppressor Proteins , Genetics