ABSTRACT
Gliomas are the most common central nervous system tumours; they are highly aggressive and have a poor prognosis. RGS16 belongs to the regulator of G-protein signalling (RGS) protein family, which plays an important role in promoting various cancers, such as breast cancer, pancreatic cancer, and colorectal cancer. Moreover, previous studies confirmed that let-7c-5p, a well-known microRNA, can act as a tumour suppressor to regulate the progression of various tumours by inhibiting the expression of its target genes. However, whether RGS16 can promote the progression of glioma and whether it is regulated by miR let-7c-5p are still unknown. Here, we confirmed that RGS16 is upregulated in glioma tissues and that high expression of RGS16 is associated with poor survival. Ectopic deletion of RGS16 significantly suppressed glioma cell proliferation and migration both in vitro and in vivo. Moreover, RGS16 was validated as a direct target gene of miR let-7c-5p. The overexpression of miR let-7c-5p obviously downregulated the expression of RGS16, and knocking down miR let-7c-5p had the opposite effect. Thus, we suggest that the suppression of RGS16 by miR let-7c-5p can promote glioma progression and may serve as a potential prognostic biomarker and therapeutic target in glioma.
Subject(s)
Humans , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , MicroRNAs/metabolism , Glioma/genetics , Genes, Tumor Suppressor , Cell Proliferation , Gene Expression Regulation, Neoplastic , Cell Line, TumorABSTRACT
Introducción. El cáncer colorrectal tiene una alta incidencia en la población mundial. Diversas vías moleculares están involucradas en su desarrollo, entre ellas, la inestabilidad cromosómica, la inestabilidad microsatelital y la epigenética. Objetivo. Hacer la caracterización molecular de 44 individuos con cáncer colorrectal esporádico. Materiales y métodos. El análisis de mutaciones en los genes APC, KRAS, TP53 y BRAF se hizo mediante secuenciación de Sanger; la inestabilidad microsatelital se determinó mediante electroforesis capilar utilizando cinco marcadores de repetición corta en tándem (Short Tandem Repeat) y el estado de metilación del promotor del gen MLH1 se hizo con la técnica MS-PCR (Methylation-Specific PCR). Resultados. La frecuencia de mutación de los genes APC, KRAS y TP53 fue del 18,1, 25 y 4,5 %, respectivamente; las mutaciones detectadas se localizaron con mayor frecuencia en el colon derecho. La frecuencia de inestabilidad microsatelital fue del 27,2 % y el 73,1 % en los tumores con metilación en el gen MHL1, y el 91,6 % de los tumores con inestabilidad microsatelital presentaba metilación en el gen MLH1. En el grupo de tumores con estabilidad microsatelital, las mutaciones en los genes APC, KRAS y TP53 fueron más frecuentes que en el grupo de tumores con inestabilidad microsatelital. La metilación del gen MLH1 fue la alteración más predominante. Conclusiones. En los pacientes con cáncer colorrectal evaluados se demostró la presencia de alteraciones moleculares en las diferentes vías genéticas, las cuales son comunes en su carcinogénesis. Los pacientes presentaron un perfil de mutaciones diferente al de otras poblaciones. Los hallazgos obtenidos en este estudio confirman la heterogeneidad molecular descrita en el desarrollo del cáncer colorrectal.
Introduction: Colorectal cancer has a high incidence in the world population. Different molecular pathways, such as chromosomal instability, microsatellite instability, and epigenetics are involved in its development. Objective: To perform molecular characterization in 44 individuals with sporadic colorectal cancer. Materials and methods: We conducted mutation analyses of the APC, KRAS, TP53 y BRAF genes using Sanger sequencing techniques; microsatellite instability was determined by capillary electrophoresis with five STR genetic markers while the methylation status of the MHL1 promotor gene was analyzed using methylation-specific PCR. Results: APC, KRAS, and TP53 genes mutation frequency was 18.1%, 25%, and 4.5%, respectively; the somatic mutations detected were located more frequently in the right colon. The frequency of microsatellite instability was 27.2% and 73.1% of the tumors had the MHL1 gene methylated while 91.6% of microsatellite instability-positive tumors had the methylated MLH1 gene. The mutation profile of microsatellite stability tumors APC, KRAS, and TP53 genes was more frequent than in the microsatellite instability-positive tumors. The methylation of the MLH1 gene was the most predominant molecular alteration. Conclusions: We identified molecular alterations in different genetic pathways of the colorectal cancer patients evaluated, which are common in the carcinogenesis of this cancer. These patients showed a different mutational profile compared to other populations. Our findings confirm the molecular heterogeneity described in the development of colorectal cancer.
Subject(s)
Colorectal Neoplasms/genetics , Oncogenes , Genes, Tumor Suppressor , Genetic Heterogeneity , Microsatellite Instability , EpigenomicsABSTRACT
Introducción: El cáncer pulmonar constituye un serio problema de salud mundial por su elevada prevalencia y mortalidad. En la carcinogénesis pulmonar están implicados oncogenes y genes supresores tumorales, que en una compleja interacción con factores ambientales favorecen la transformación cancerosa. Objetivo: Describir los principales genes implicados en el cáncer pulmonar. Métodos: Se buscaron referencias en las bases de datos PubMed Central, Annual Reviews y SciELO. Se revisaron preferentemente los artículos originales, las revisiones bibliográficas, las revisiones sistemáticas y los metaanálisis de los últimos cinco años. Análisis e integración de la información: En la carcinogénesis pulmonar se involucran los oncogenes JUN, FOS, ABL1, BRAF, RAF1, GNAS, KRAS, NRAS, HRAS, CSF 1R, MYC, EGFR, MET, ALK, CCNE1, DDR2, ERBB3, FGFR1, MDM2, ROS1, SOX2 y TP63 y los genes supresores tumorales TP53, CDKN2A, CDKN1A, RB1, CDK2AP1, ATM, ERCC2, BRCA1, CCND1, STK11, PDLIM2, PTEN, ARID1A, ASCL4, CUL3, EP300, KEAP1, KMT2D, NF1, NOTCH1, RASA1, ETD2 y SMARCA4. El conocimiento de la genética molecular del cáncer pulmonar es importante para la identificación de biomarcadores diagnósticos y pronósticos más eficaces y para el diseño de fármacos diana sobre genes específicos(AU)
Introduction: Lung cancer is a serious global health problem due to its high prevalence and mortality. Lung carcinogenesis involves oncogenes and tumor suppressor genes which interact in complex manners with environmental factors, paving the way for the cancerous transformation. Objective: Describe the main genes involved in lung cancer. Methods: References were searched for in the databases PubMed Central, Annual Reviews and SciELO. Particular attention was paid to original papers, bibliographic reviews, systematic reviews and meta-analyses published in the last five years. Data analysis and integration: Lung carcinogenesis involves the oncogenes JUN, FOS, ABL1, BRAF, RAF1, GNAS, KRAS, NRAS, HRAS, CSF 1R, MYC, EGFR, MET, ALK, CCNE1, DDR2, ERBB3, FGFR1, MDM2, ROS1, SOX2 and TP63, and the tumor suppressor genes TP53, CDKN2A, CDKN1A, RB1, CDK2AP1, ATM, ERCC2, BRCA1, CCND1, STK11, PDLIM2, PTEN, ARID1A, ASCL4, CUL3, EP300, KEAP1, KMT2D, NF1, NOTCH1, RASA1, ETD2 and SMARCA4. Knowledge about the molecular genetics of lung cancer is important to identify more efficient diagnostic and prognostic biomarkers and to design targeted drugs for specific genes(AU)
Subject(s)
Humans , Oncogenes , Biomarkers , Genes, Tumor SuppressorABSTRACT
BACKGROUND@#The pathogenesis of osteosarcoma (OS) is still unclear, and it is still necessary to find new targets and drugs for anti-OS. This study aimed to investigate the role and mechanism of the anti-OS effects of miR-296-5p.@*METHODS@#We measured the expression of miR-296-5p in human OS cell lines and tissues. The effect of miR-296-5p and its target gene staphylococcal nuclease and tudor domain containing 1 on proliferation, migration, and invasion of human OS lines was examined. The Student's t test was used for statistical analysis.@*RESULTS@#We found that microRNA (miR)-296-5p was significantly downregulated in OS cell lines and tissues (control vs. OS, 1.802 ± 0.313 vs. 0.618 ± 0.235, t = 6.402, P < 0.01). Overexpression of miR-296-5p suppressed proliferation, migration, and invasion of OA cells. SND1 was identified as a target of miR-296-5p by bioinformatic analysis and dual-luciferase reporter assay. Overexpression of SND1 abrogated the effects induced by miR-296-5p upregulation (miRNA-296-5p vs. miRNA-296-5p + SND1, 0.294 ± 0.159 vs. 2.300 ± 0.277, t = 12.68, P = 0.003).@*CONCLUSION@#Our study indicates that miR-296-5p may function as a tumor suppressor by targeting SND1 in OS.
Subject(s)
Humans , Bone Neoplasms/genetics , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Endonucleases/genetics , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor , MicroRNAs/genetics , Osteosarcoma/geneticsABSTRACT
El síndrome de Brooke-Spiegler (SBS) es una entidad rara, autosómica dominante, que ocurre por mutaciones del gen CYLD, el cual funciona como supresor de tumores. Se presenta el caso de una mujer de 50 años de edad, con historia de aparición de lesiones características de tricoepiteliomas que predominaban en nariz, región interciliar y mentón, que iniciaron desde los 14 años de edad. Desde hace 5 años refiere aumento del tamaño de lesiones en alas nasales, y una lesión en punta nasal de 2 años de evolución. Al realizarse una correlación clínica e histológica, asociada a los antecedentes familiares de la madre y hermano de la paciente, se concluyó que el cuadro clínico era compatible con tricoepitelioma múltiple familiar, una variante especial del SBS, en este caso asociado a carcinoma basocelular, que aunque no es un hallazgo común, se ha visto que se puede presentar en esta enfermedad. El diagnóstico preciso de SBS requiere de una correlación clínico-histológica, y se debe hacer un seguimiento clínico cercano para detectar cambios en las lesiones en piel, que puedan indicar una transformación maligna
Brooke-Spiegler syndrome (BSS) is a rare autosomal dominant condition that occurs due to mutations in the CYLD gene, which functions as a tumor suppressor gene. The case of a 50-year-old woman with a history of characteristic trichoepitheliomas predominantly in the nose, glabella and chin that began at 14 years of age is presented. She reports an increase in the size of the nasal ala lesions for the past 5 years, and the appearance of a new lesion in the nasal tip 2 years ago. When performing a clinical and histological correlation, associated with family history in both the mother and brother, it was concluded that the diagnosis was compatible with multiple familial trichoepithelioma, a special variant of BSS, associated in this case with basal cell carcinoma, that although not a common finding, has been seen to coexist in this disease. The diagnosis of BSS requires a clinical and histological correlation, and a close clinical follow-up must be performed to detect changes in the skin lesions that may indicate malignant transformation
Subject(s)
Carcinoma, Basal Cell , Genes, Tumor Suppressor , Machado-Joseph Disease , Acrospiroma , Carcinoma, Adenoid Cystic , Deubiquitinating Enzyme CYLDABSTRACT
El virus de Epstein Barr (VEB) se encuentra presente en el 100% de los casos de linfoma T/NK extranodal de tipo nasal (ENKTL) y juega un papel importante en la etiopatogenia de esta enfermedad. El objetivo de esta revisión es actualizar el conocimiento de las vías moleculares genéticas y epigenéticas utilizadas por el VEB en la oncogenesis del ENKTL. Para ello se realizó una revisión de la literatura, en las bases de datos de PubMed y Google Scholar, sobre los mecanismos que utilizan las proteínas virales como la proteína de membrana latente (LMP1) y el antígeno nuclear Epstein Barr 1 (EBNA1) para activar proteínas antiapoptóticas del huésped y pro-teínas relacionadas a proliferación celular, a través de las vías moleculares JAK/STAT (Janus quinasas/señales de transducción y activación de proteínas de transcripción), NF-κB (el factor nuclear potenciador de las cadenas ligeras kappa de las células B activadas) EZHZ2 (Enhancer of Zeste 2 Polycomb repressive Complex 2) y PI3K/Akt (Fosfoinositido 3 quinasa/proteína quinasa B); también se revisó el papel de las proteínas virales BNLF2a, BILF y BDLF3 en la evasión inmune del virus. También LMP1 aumenta la expresión de PDL-1 (ligando de la muerte celular programada), contribuyendo a la disminución de la respuesta inmunológica. A nivel epigenético se abordan los cambios del perfil de metilación en las áreas promotoras de genes supresores de tumor y se explica la función de los miARN de VEB que participan inhibiendo genes supresores de tumor o activando genes que aumentan la proliferación.
Epstein Barr virus (EBV) is present in 100% of cases of nasal-type extranodal NK/T cell lymphoma (ENKTL). It plays an important role in the etiopathogenesis of this disease. The objective of this review is to update the knowledge of the genetic and epigenetic molecular pathways used by EBV in the oncogenesis of ENKTL. To this end, a literature review was carried out in the PubMed and Google Scholar databases on the mechanisms used by viral proteins such as latent membrane protein (LMP1) and Epstein Barr 1 nuclear antigen (EBNA1) to activate host antiapoptotic proteins avoiding cell death and activating cell proliferation, through the molecular pathways JAK/STAT (Janus kinases/signal transduction and activation of transcription proteins), NF-κB (the nuclear factor enhancing the kappa light chains of activated B cells) EZHZ2 pathways (Enhancer of Zeste 2 Polycomb repressive Complex 2) and PI3K/Akt (Phosphoinositide 3 kinase protein kinase B). The role of the viral proteins: BNLF2a, BILF and BDLF3 in the virus immune evasion. It is currently recognized that LMP1 increases the expression of PDL-1 (programmed cell death ligand), contributing to the decrease in the immune response. Thus, the epigenetic changes in the methylation profile in the promoter areas of tumor suppressor genes, was also reviewed. Finally role of EBV miRNAs participate in inhibiting tumor suppressor genes or activating genes that increase proliferation.
Subject(s)
Humans , Herpesvirus 4, Human , Lymphoma, Extranodal NK-T-Cell/complications , Genes, Tumor Suppressor , Apoptosis , Epstein-Barr Virus InfectionsABSTRACT
BACKGROUND: Basal-like breast cancer (BLBC) or triple-negative breast cancer (TNBC) is an aggressive and highly metastatic subtype of human breast cancer. The present study aimed to elucidate the potential tumor-suppressive function of MATR3, an abundant nuclear protein, in BLBC/TNBC, whose cancer-relevance has not been characterized. METHODS: We analyzed in vitro tumorigenecity by cell proliferation and soft agar colony formation assays, apoptotic cell death by flow cytometry and Poly (ADP-ribose) polymerase (PARP) cleavage, epithelial-mesenchymal transition (EMT) by checking specific EMT markers with real-time quantitative PCR and in vitro migration and invasion by Boyden Chamber assays. To elucidate the underlying mechanism by which MATR3 functions as a tumor suppressor, we performed Tandem affinity purification followed by mass spectrometry (TAP-MS) and pathway analysis. We also scrutinized MATR3 expression levels in the different subtypes of human breast cancer and the correlation between MATR3 expression and patient survival by bioinformatic analyses of publicly available transcriptome datasets. RESULTS: MATR3 suppressed in vitro tumorigenecity, promoted apoptotic cell death and inhibited EMT, migration, and invasion in BLBC/TNBC cells. Various proteins regulating apoptosis were identified as MATR3-binding proteins, and YAP/TAZ pathway was suppressed by MATR3. MATR3 expression was inversely correlated with the aggressive and metastatic nature of breast cancer. Moreover, high expression levels of MATR3 were associated with a good prognosis of breast cancer patients. CONCLUSIONS: Our data demonstrate that MATR3 functions as a putative tumor suppressor in BLBC/TNBC cells. Also, MATR3 potentially plays a role as a biomarker in predicting chemotherapy-sensitivity and patient survival in breast cancer patients.
Subject(s)
Humans , Female , Genes, Tumor Suppressor , RNA-Binding Proteins/genetics , Nuclear Matrix-Associated Proteins/genetics , Triple Negative Breast Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Cell Movement , Apoptosis , Cell Line, Tumor , Cell Proliferation , Epithelial-Mesenchymal TransitionABSTRACT
BACKGROUND: Melanoma is one of the major types of skin cancer. The metastatic melanoma is among the most lethal forms of malignant skin tumors. We hereby aimed to characterize a novel microRNA (miR) in the metastatic melanoma model. METHODS: First, we evaluated the expression of miR-107 in melanoma cells and tumor tissues. The comparison between primary and metastatic cancer tissues was also accessed. Next, we examined the impact of miR-107 on melanoma cell proliferation, cell cycle, colony formation, apoptotic activity, migration and matrix invasion. A downstream target of miR-107 was also predicted and validated functionally in melanoma cells. RESULTS: Our findings showed miR-107 was significantly downregulated in melanoma. Its expression was lowest in metastatic form. Over-expression of miR-107 reduced melanoma cell proliferation, migration and invasion. POU3F2 was identified as the downstream target of miR-107. Over-expression of POU3F2 antagonized miR-107-mediated inhibitory effect on melanoma cells. CONCLUSION: Our study has reported miR-107 as a novel tumor suppressive factor in the metastatic melanoma model. It has provided new avenue to manage melanoma and improve the survival rate in the advanced stage.
Subject(s)
Humans , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor , MicroRNAs/genetics , POU Domain Factors/genetics , Melanoma/genetics , Tumor Stem Cell Assay , Cell Movement , Cell Line, Tumor , Cell ProliferationABSTRACT
As proteínas INGs (inhibitor of growth gene) desempenham papel de supressoras tumorais e podem agir por vias dependentes, ou independentes, da p53 na sinalização do ciclo celular e da apoptose. Este trabalho investigou, por meio de imuno-histoquímica, a correlação entre a expressão das proteínas INGs e a expressão da proteína p53 em ceratocistos odontogênicos (20), TOAs (20) e ameloblastomas sólidos (20). Os espécimes foram submetidos à marcação utilizando os anticorpos anti-Ing3, anti-Ing4, anti-Ing5 e anti-p53. Foi realizada análise quantitativa levando-se em consideração a localização citoplasmática e/ou nuclear para as proteínas INGs e a localização nuclear para a proteína p53. A análise da imunoexpressão das proteínas ING1 e ING2 foi realizada em um estudo prévio e os resultados foram considerados apenas para a análise de correlação com as proteínas estudadas neste estudo. Os dados foram analisados pelo Statistical Package for Social Sciences para Windows (SPSS versão 22.0; IBM, USA). Para a comparação da imunoexpressão entre os grupos de lesões foi utilizado o teste de Kruskal Wallis, e para a investigação das correlações foi utilizado o teste de Spearman. Foram considerados significativos os valores de p ≤ 0.05. O presente estudo evidenciou redução da expressão nuclear e citoplasmática das proteínas ING3, ING4 e ING5 em ceratocistos odontogênicos (COs) e ameloblastomas (AMBs). Além disso, em alguns casos, a perda da expressão nuclear das INGs esteve negativamente correlacionada à expressão da proteína p53. As análises de correlação entre as proteínas INGs indicam a existência de mecanismos compensatórios entre as proteínas INGs em folículos dentários (FDs) e tumores odontogênicos adenomatoides (TOAs), estes mecanismos parecem ser menos evidentes em COs e AMBs. Observou-se redução na expressão da proteína ING3 em AMBs (p=0,003); redução na expressão da proteína ING4, tanto em AMBs (p=0,02) quanto em COs (p=0,001); e uma redução da expressão nuclear da proteína ING5 nos COs (p=0,09) e nos AMBs (p=0,012). Foram evidenciadas correlações positivas entre a expressão nuclear da p53 com a expressão citoplasma/núcleo da proteína ING1 (r=0,603; p=0,05) em COs, e com a expressão citoplasma/ núcleo das proteínas ING3 (r=0,475; p=0,034) e ING4 (r=0,448; p=0,047) em AMBs. Por fim, os resultados deste estudo sugerem que a redução na expressão nuclear das proteínas INGs pode ser um evento envolvido na etiopatogênese de lesões odontogênicas mais agressivas, e que a redução da expressão nuclear/citoplasmática das proteínas INGs não está relacionada ao aumento expressão da p53 em COs e AMBs, o que sugere que a expressão destas proteínas deve resultar em alterações funcionais de maneira independente da p53 em lesões odontogênicas (AU).
INGs (inhibitor of growth gene) proteins play a role of tumor suppressors and can act via p53-dependent or independent pathways in signaling cell cycle and apoptosis. The aim of this study is to evaluate correlation between expression of proteins of ING proteins and expression of protein p53 in dental follicles (DF), odontogenic keratocysts (OK), adenomatoid odontogenic tumors (AOT) and solid ameloblastomas (AMBs). The sample was intentional and non-probabilistic, consisting of 20 cases of solid AMBs, 20 cases of AOT, 20 cases of OKs and 10 samples of DFs. The specimens were subjected to immunohistochemical method, using antibodies anti-Ing3, anti-Ing4, anti-Ing5 and antip53. Quantitative analysis was performed taking into account cytoplasmic and / or nuclear location for ING proteins and nuclear location for the p53 protein. The analysis of ING1 and ING2 immunoexpressions was performed in a previous study and the results were considered only for the correlation analysis. Data were analyzed by Statistical Package for Social Sciences for Windows (SPSS version 22.0; IBM, USA). Kruskal Wallis test was used to compare the immunoexpression between the groups of lesions, and Spearman test was used to investigate correlations. Values of p ≤ 0.05 were considered significant. This study showed a reduction in nuclear and cytoplasmic expression of ING3, ING4 and ING5 in odontogenic keratocysts (OKs) and ameloblastomas (AMBs). In addition, in some cases, loss of INGs nuclear expression was negatively correlated with p53 expression. Correlation analyzes may indicate existence of compensatory mechanisms between all the ING proteins in dental follicles (FDs) and adenomatoid odontogenic tumors (TOAs). These mechanisms seem to be less evident in COs and AMBs. The results of this study showed a reduction in ING3 expression in AMBs (p = 0.003); a reduction in ING4 expression, in OKs (p = 0.02) and in AMBs (p = 0.001); and a reduction in ING5 nuclear expression, also in OK (p = 0.09) and in AMBs (p = 0.012). Positive correlations were found between p53 nuclear expression with ING1 cytoplasm / nucleus expression (r = 0.603; p = 0.05) in OKs, and with ING3 cytoplasm / nucleus expression (r = 0.475; p = 0.034) and also ING4 cytoplasm / nucleus expression (r = 0.448; p = 0.047) in AMBs. Finally, this study suggests that reduction in the expression of INGs proteins seems to be an event that occurred in etiopathogenesis of more aggressive odontogenic lesions. Futhermore, nuclear / cytoplasmic expression of INGs proteins is not related to increase in p53 expression in OKs and AMBs, which indicates that loss of expression of these proteins may results in functional changes independently of p53 (AU).
Subject(s)
Odontogenic Tumors/pathology , Genes, Tumor Suppressor , Adenomatoid Tumor/pathology , Inhibitor of Apoptosis Proteins , Immunohistochemistry/methods , Photomicrography/instrumentation , Odontogenic Cysts/pathology , Statistics, Nonparametric , Observational Studies as Topic/methodsABSTRACT
ABSTRACT Pterygium pathogenesis has been mainly asso ciated with UV light exposure; however, this association remains quite controversial. The complete mechanism of pterygium also remains to be clarified. Factors such as inflammation, viral infection, oxidative stress, DNA methylation, inflammatory mediators, extracellular matrix modulators, apoptotic and oncogenic proteins, loss of heterozygosity, microsatellite instability, lymphangiogenesis, epithelial-mesenchymal cell transition, and alterations in cholesterol metabolism have been identified as causes. Several studies aimed to clarify the molecular mechanisms underlying the growth and proliferation of pterygium. Understanding its molecular basis provides new potential therapeutic targets for its prevention and treatment. A comprehensive search of the databases, namely, MedLine, EMBASE, and LILACS, was conducted with the following key words: pterygium, epidemiology, pathogenesis, biomarkers, and review. This review describes the epidemiology, clinical presentation, and current investigation of biological mediators involved in pterygium development.
RESUMO A patogênese do pterígio tem sido relacionada, prin cipalmente, à exposição à luz ultravioleta, mas esta asso ciação permanece bastante controversa. O mecanismo completo do pte rígio também permanece por esclarecer. Fatores como inflamação, infecção viral, estresse oxidativo, metilação do DNA, mediadores inflamatórios, moduladores de matriz extracelular, proteínas apoptóticas e oncogênicas, perda de heterozigose, instabilidade de microssatélites, linfangiogênese, transição celular epitelial-mesenquimal e alterações no metabolismo do colesterol tem sido identificados como causas. Diversos estudos visam esclarecer os mecanismos moleculares subjacentes ao crescimento e proliferação do pterígio. Entender sua base mo lecular fornece novos alvos terapêuticos potenciais para sua prevenção e tratamento. Uma busca abrangente nas bases de dados, a saber, MedLine, EMBASE e LILACS, foi realizada com as seguintes palavras-chave: pterígio; epidemiologia; patogênese; biomarcadores e revisão. Esta revisão descreve a epidemiologia, apresentação clínica e a atual investigação de mediadores biológicos envolvidos no desenvolvimento do pterígio.
Subject(s)
Humans , Male , Female , Pterygium/genetics , Pterygium/metabolism , Genetic Markers , Gene Expression , Genes, Tumor Suppressor , Apoptosis Regulatory Proteins , Extracellular MatrixABSTRACT
OBJECTIVE@#To explore whether tumor suppressor gene Foxo1 and PTEN play a critical role in the tumorigenesis of mouse natural killer-cell lymphoma.@*METHODS@#NKp46-iCre mice were crossed with mice carrying floxed Foxo1 alleles (Foxo1) as well as floxed PTEN alleles (PTEN) to generate mice in which Foxo1 and PTEN in NK cells were knock-out, referred as Foxo1PTEN. The growth and development of the mice and tumor formation were observed. The flow cytometry was used to detect the percentages of NK cells in main lymphatic organs. B16F10 metanoma model of tumor metastasis was utilized to investigate NK cell-mediated tumor surveillance in vivo after NK cells special deletion of Foxol and PTEN.@*RESULTS@#The mouse model with NK cell-special Foxo1 and PTEN double knockout was established. Compared with control group (Foxo1PTEN mice), Foxo1PTEN mice were born alive and appeared to be healthy over a period of 46 weeks. No spontaneous tumor formation was observed at this stage. There were no significant differences in NK cell percentages of gated lymphocytes from various organs including blood, bone marrow, peripheral lymph node and spleen between Foxo1PTEN mice and Foxo1PTEN mice [PB: 4.76%±0.46% vs 4.17%±0.64% (P>0.05, n=8); BM: 1.13%±0.23% vs 1.31%±0.10% (P>0.05, n=8) ; LN: 0.50%±0.10% vs 0.85%±0.20% (P>0.05, n=8); SP: 4.41%±0.65% vs 3.50%±0.24% (P>0.05, n=8)]. B16F10 melanoma metastasis model of tumor was established, No differences in median survival time were observed in the 2 types of mice (P>0.05, n=13).@*CONCLUSION@#The simultaneous deletion of the Foxo1 and PTEN genes may not plays significant role in the tumorigenesis of mouse natural killer-cell lymphoma and NK cell-mediated tumor surveillance in vivo.
Subject(s)
Animals , Mice , Cell Transformation, Neoplastic , Forkhead Box Protein O1 , Genes, Tumor Suppressor , Killer Cells, Natural , Lymphoma , Mice, KnockoutABSTRACT
OBJECTIVE@#To explore the role of miR-593 in regulating the proliferation of colon cancer cells and the molecular mechanism.@*METHODS@#Bioinformatics analysis identified PLK1 as the possible target gene of miR-593. Luciferase assay was employed to verify the binding between miR-593 and PLK1, and qRT-PCR and Western blotting were used to verify that PLK1 was the direct target gene of miR-593. CCK-8 assay was performed to test the hypothesis that miR-593 inhibited the proliferation of colon cancer cells by targeting PLK1.@*RESULTS@#Luciferase assay identified the specific site of miR-593 binding with PLK1. Western blotting showed a significantly decreased expression of PLK1 in the colon cancer cells transfected with miR-593 mimics and an increased PLK1 expression in the cells transfected with the miR-593 inhibitor as compared with the control cells ( < 0.05). The results of qRT-PCR showed no significant differences in the expression levels of PLK1 among the cells with different treatments ( > 0.05). The cell proliferation assay showed opposite effects of miR-593 and PLK1 on the proliferation of colon cancer cells, and the effect of co-transfection with miR-593 mimic and a PLK1-overexpressing plasmid on the cell proliferation was between those in PLK1 over-expressing group and miR-593 mimic group.@*CONCLUSIONS@#miR-593 inhibits the proliferation of colon cancer cells by down-regulating PLK1 and plays the role as a tumor suppressor in colon cancer.
Subject(s)
Humans , Binding Sites , Cell Cycle Proteins , Genetics , Metabolism , Cell Line, Tumor , Cell Proliferation , Colonic Neoplasms , Metabolism , Pathology , Down-Regulation , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor , In Vitro Techniques , MicroRNAs , Genetics , Metabolism , Protein Serine-Threonine Kinases , Genetics , Metabolism , Proto-Oncogene Proteins , Genetics , Metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sincalide , Metabolism , TransfectionABSTRACT
OBJECTIVE@#To investigate the effect of the long chain non-coding RNA H19 (lncRNA H19) on the invasion and migration of oral cancer cells and its related molecular mechanism.@*METHODS@#The expression levels of lncRNA H19, miR-107, and cyclin-dependent kinase 6 (CDK6) in the immortalized oral epithelial cell line HIOEC and the oral cancer cell line CAL27 were detected by real-time quantitative polymerase chain reaction. CAL27 cells were transfected with siRNA H19, miR-107 mimics, pcDNA H19, or anti-miR-107, and the effects of H19 and miR-107 on the invasion and migration of cells were examined via Transwell assay. The TargetScan database predicted the targeting of H19, miR-107, and CDK6. Double luciferase reporter gene assay was performed to detect interactions among H19, miR-107, and CDK6. Western blot analysis was conducted to examine the effects of H19 and miR-107 on the protein level of the target gene CDK6.@*RESULTS@#Compared with that in HIOEC cells, the expression of H19 was significantly increased in CAL27 cells (P<0.05). After transfection with siRNA H19, the expression of H19 decreased, and the invasion and migration ability of CAL27 cells were inhibited (P<0.05). H19 could bind specifically to the 3'-UTR of miR-107 to modulate the expression of miR-107. Compared with that in HIOEC cells, the expression of miR-107 significantly decreased in CAL27 cells (P<0.05). The expression of miR-107 increased after transfection with siRNA H19, and anti-mir-107 co-transfection could promote the invasion and migration ability of siRNA H19 in CAL27 cells (P<0.05). Compared with that in HIOEC cells, CDK6 expression significantly increased in CAL27 cells (P<0.05), and the expression level of the gene was coregulated by H19 and miR-107 (P<0.05).@*CONCLUSIONS@#lncRNA H19 plays an important role in the development of oral cancer. It can regulate the invasion and migration of oral cancer cells by targeting the miR-107/CDK6 signaling axis.
Subject(s)
Humans , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor , MicroRNAs , Mouth Neoplasms , RNA, Long NoncodingABSTRACT
BACKGROUND: BRCA1 mutated breast cancer cells exhibit the elevated cell proliferation and the higher metastatic potential. G protein-coupled receptor 30 (GPR30) has been shown to regulate growth of hormonally responsive cancers, such as ovarian and breast cancers, and high expression of GPR30 is found in estrogen receptor (ER)-negative breast cancer cells. ER-negative breast cancer patients often have a mutation in the tumor suppressor gene, BRCA1. This study explored antiproliferative effects of genistein, a chemopreventive isoflavone present in legumes, and underlying molecular mechanisms in triple negative breast cancer cells with or without functionally active BRCA1.METHODS: Expression of BRCA1, GPR30 and Nrf2 was measured by Western blot analysis. Reactive oxygen species (ROS) accumulation was monitored by using the fluorescence-generating probe, 2’,7’-dichlorofluorescein diacetate. The effects of genistein on breast cancer cell viability and proliferation were assessed by the MTT, migration and clonogenic assays.RESULTS: The expression of GPR30 was dramatically elevated at both transcriptional and translational levels in BRCA1 mutated breast cancer cells compared to cells with wild-type BRCA1. Notably, there was diminished Akt phosporylation in GPR30 silenced cells. Treatment of BRCA1 silenced breast cancer cells with genistein resulted in the down-regulation of GPR30 expression and the inhibition of Akt phosphorylation as well as the reduced cell viability, migration and colony formation. Genistein caused cell cycle arrest at the G₂/M phase in BRCA1-mutant cells through down-regulation of cyclin B1 expression. Furthermore, BRCA1-mutant breast cancer cells exhibited higher levels of intracellular ROS than those in the wild-type cells. Genistein treatment lowered the ROS levels through up-regulation of Nrf2 expression.CONCLUSIONS: Lack of functional BRCA1 activates GPR30 signaling, thereby stimulating Akt phosphorylation and cell proliferation. Genistein induces G2/M phase arrest by down-regulating cyclin B1 expression, which is attributable to its suppression of GPR30 activation and Akt phosphorylation in BRCA1 impaired breast cancer cells.
Subject(s)
Humans , Blotting, Western , Breast Neoplasms , Breast , Cell Cycle Checkpoints , Cell Proliferation , Cell Survival , Cyclin B1 , Down-Regulation , Estrogens , Fabaceae , Genes, Tumor Suppressor , Genistein , Phosphorylation , Reactive Oxygen Species , Triple Negative Breast Neoplasms , Up-RegulationABSTRACT
PTEN hamartoma tumor syndrome is a spectrum of disorders characterized by unique phenotypic features including multiple hamartomas caused by mutations of the tumor suppressor gene PTEN. Cowden syndrome and Bannayan–Riley–Ruvalcaba syndrome are representative diseases, and both have several common clinical features and differences. Because PTEN mutations are associated with an increased risk of malignancy including breast, thyroid, endometrial, and renal cancers, cancer surveillance is an important element of disease management. We report a germline mutation of the PTEN (c.723dupT, exon 7) identified in a young woman with a simultaneous occurrence of breast cancer, dermatofibrosarcoma protuberans, and follicular neoplasm. This case suggests that it is critical for clinicians to recognize the phenotypic features associated with these syndromes to accurately diagnose them and provide preventive care.
Subject(s)
Female , Humans , Breast , Breast Neoplasms , Dermatofibrosarcoma , Disease Management , Exons , Genes, Tumor Suppressor , Germ-Line Mutation , Hamartoma , Hamartoma Syndrome, Multiple , Kidney Neoplasms , Thyroid GlandABSTRACT
BACKGROUND: We previously reported the frequent neurofibromatosis 2 (NF2) gene mutations in anaplastic thyroid cancers in association with the BRAF V600E mutation. We aimed to investigate the role of NF2 in thyroid cancer with BRAF mutation. METHODS: To identify the function of NF2 in thyroid cancers, we investigated the changes in cell proliferation, colon formation, migration and invasion of thyroid cancer cells (8505C, BHT101, and KTC-1) with BRAF V600E mutation after overexpression and knock-down of NF2. We also examined how cell proliferation changed when NF2 was mutagenized. Human NF2 expression in papillary thyroid carcinoma (PTC) was analyzed using the The Cancer Genome Atlas (TCGA) data. RESULTS: First, NF2 was overexpressed in 8505C and KTC-1 cells. Compared to control, NF2 overexpressed group of both thyroid cancer cells showed significant inhibition in cell proliferation and colony formation. These results were also confirmed by cell migration and invasion assay. After knock-down of NF2 in 8505C cells, there were no significant changes in cell proliferation and colony formation, compared with the control group. However, after mutagenized S288* and Q470* sites of NF2 gene, the cell proliferation increased compared to NF2 overexpression group. In the analysis of TCGA data, the mRNA expression of NF2 was significantly decreased in PTCs with lateral cervical lymph node (LN) metastasis compared with PTCs without LN metastasis. CONCLUSION: Our study suggests that NF2 might play a role as a tumor suppressor in thyroid cancer with BRAF mutation. More studies are needed to elucidate the mechanism how NF2 acts in thyroid cancer with BRAF mutation.
Subject(s)
Humans , Cell Movement , Cell Proliferation , Colon , Genes, Neurofibromatosis 2 , Genes, Tumor Suppressor , Genome , Lymph Nodes , Neoplasm Metastasis , Neurofibromatosis 2 , RNA, Messenger , Thyroid Carcinoma, Anaplastic , Thyroid Gland , Thyroid NeoplasmsABSTRACT
A variety of clonal cytogenetic abnormalities have been reported in aggressive natural killer (NK)-cell lymphoma and leukemia. Recent chromosomal microarray studies have shown both gain and loss of 1q and loss of 7p as recurrent abnormalities in aggressive NK-cell leukemia. Here, we report a case of aggressive NK-cell leukemia with complex chromosomal gains and losses, as confirmed by chromosomal microarray analysis. The patient showed an aggressive clinical course, which was complicated by hemophagocytic lymphohistiocytosis. Conventional cytogenetic analysis revealed trisomy 3 and 1q gain only. However, chromosomal microarray analysis detected an additional gain of 1q21.1–q24.2 and a loss of 1q24.2–q31.3. These abnormal lesions might play a role in the pathogenesis of aggressive NK-cell leukemia by inactivating tumor suppressor genes or by activating oncogenes. These results suggest that chromosomal microarray analysis may be used to provide further genetic information for patients with hematological malignancies, including aggressive NK-cell leukemia.
Subject(s)
Humans , Chromosome Aberrations , Cytogenetic Analysis , Genes, Tumor Suppressor , Hematologic Neoplasms , Leukemia , Lymphohistiocytosis, Hemophagocytic , Lymphoma , Microarray Analysis , Oncogenes , TrisomyABSTRACT
PURPOSE: Tumor protein p53-regulated apoptosis-inducing protein 1 (TP53AIP1) functions in various cancers. We studied the effect and molecular mechanism of TP53AIP1 in breast cancer. METHODS: The degree of correlation between TP53AIP1 expression and overall survival in patients with breast cancer was obtained from the online The Cancer Genome Atlas database. Six of the TP53AIP1 levels in the tumor and adjacent non-tumor tissues randomly selected from 38 breast cancer patients were determined. Transgenic technology was used to enhance the expression of TP53AIP1 in breast cancer cell lines, MDA-MB-415 and MDA-MB-468, and to observe the effects of gene overexpression on the proliferation, cell cycle, and apoptosis of breast cancer cells. The molecular mechanism of association between cell cycle- and apoptosis-related factors and the phosphoinositide 3-kinases/protein kinase B (PI3K/Akt) pathway was also studied. RESULTS: The messenger RNA and protein expression levels of TP53AIP1 in cancer tissues were significantly lower than those in the control group. TP53AIP1 overexpression inhibits cell viability. The mechanism of TP53AIP1 inhibition of proliferation and growth of breast cancer cells includes cell cycle arrest, apoptosis promotion (p < 0.01), promotion of the expression of cleaved-caspase-3 (p < 0.01), cleaved-caspase-9 (p < 0.01), B cell lymphoma/leukemia-2 (Bcl-2)-associated X protein, and p53 (p < 0.01), and the inhibition of Bcl-2, Ki67, and PI3K/Akt pathways (p < 0.01). CONCLUSION: TP53AIP1 may be a novel tumor suppressor gene in breast cancer and can potentially be used as an effective target gene for the treatment of breast cancer.
Subject(s)
Humans , Apoptosis , Breast Neoplasms , Breast , Cell Cycle Checkpoints , Cell Line , Cell Proliferation , Cell Survival , Genes, p53 , Genes, Tumor Suppressor , Genome , Phosphotransferases , RNA, MessengerABSTRACT
Medulloblastoma is considered one of the most threatening malignant brain tumors with an extremely high mortality rate in children. In the medulloblastoma, there are several genes and mutations found to work in an unregulated manner that works together to push the cells into a cancerous state. With the discovery of non-coding RNAs such as microRNAs (miRNAs), it has been shown that a different layer of gene regulations may be disrupted which would cause cancer. This fact led scientists to put their focus on the role of miRNAs in cancer. A mature miRNA contains a seed sequence which gives the miRNA to identify and attach to the interest mRNA; this attachment may lead degradation of mRNA or suppress of translation of the mRNA. The expression of miRNAs in medulloblastoma shows that some of these non-coding RNAs are overexpressed (OncomiRs) which help cells to proliferate and keep their stemness features. On the other hand, there are other forms of these miRNAs which normally inhibit cell proliferation and promote cell differentiation (tumor suppressor). These are down-regulated during cancer progression. In this systematic review, we attempted to gather several important studies on miRNAs’ role in medulloblastoma tumors and the importance of these non-coding RNAs in the future study of cancer.
Subject(s)
Child , Humans , Brain Neoplasms , Cell Differentiation , Cell Proliferation , Genes, Tumor Suppressor , Hand , Medulloblastoma , MicroRNAs , Mortality , Oncogenes , RNA, Messenger , RNA, Untranslated , Social Control, FormalABSTRACT
No abstract available.