RESUMEN
Ten-eleven translocation 1 (TET1) is a methylcytosine dioxygenase involved in active DNA demethylation. In our previous study, we demonstrated that TET1 reprogrammed the ovarian cancer epigenome, increased stem properties, and activated various regulatory networks, including metabolic networks. However, the role of TET1 in cancer metabolism remains poorly understood. Herein, we uncovered a demethylated metabolic gene network, especially oxidative phosphorylation (OXPHOS). Contrary to the concept of the Warburg effect in cancer cells, TET1 increased energy production mainly using OXPHOS rather than using glycolysis. Notably, TET1 increased the mitochondrial mass and DNA copy number. TET1 also activated mitochondrial biogenesis genes and adenosine triphosphate production. However, the reactive oxygen species levels were surprisingly decreased. In addition, TET1 increased the basal and maximal respiratory capacities. In an analysis of tricarboxylic acid cycle metabolites, TET1 increased the levels of α-ketoglutarate, which is a coenzyme of TET1 dioxygenase and may provide a positive feedback loop to modify the epigenomic landscape. TET1 also increased the mitochondrial complex I activity. Moreover, the mitochondrial complex I inhibitor, which had synergistic effects with the casein kinase 2 inhibitor, affected ovarian cancer growth. Altogether, TET1-reprogrammed ovarian cancer stem cells shifted the energy source to OXPHOS, which suggested that metabolic intervention might be a novel strategy for ovarian cancer treatment.
RESUMEN
OBJECTIVE: Although a large number of endometrial cancer patients are cured with surgery alone, there are significant numbers of patients with more aggressive variants of endometrial carcinoma for whom the prognosis remains poor. We investigated the effects of prevalence, histotypes, and immunohistochemical profiles on prognostic value in a hospital-based population. MATERIALS AND METHODS: A retrospective study of surgically resected primary endometrial carcinoma was included. Immunohistochemical stains were performed on formalin-fixed paraffin-embedded tissue microarray sections for ß-Catenin, estrogen receptor (ER), progesterone receptor (PR), HER-2, MLH1, MSH2, MSH6, PMS2, and p53. RESULTS: Loss of mismatch repair expression was detected in 25.4% of samples (29/114, mean age 57 years) of the tumors. The following loss of expression was observed in patients: MLH1/PMS2 in 16.6% of patients, MSH6 in 7.0% of patients, MLH1 in 0.9% of patients, and MSH6/PMS2/MLH1 in 0.9% of patients. Immunohistochemistry of p53 was analyzed for 111 patients. A total of 13 patients (11.7%, mean age 64 years) had p53-abnormal expression (absent, cytoplasmic or diffuse strong positive patterns), and more than half (9/13, 69.2%) had endometrioid histotype. Abnormalities in p53 were significantly associated with histotype (p = 0.001), advanced tumor stage (p = 0.038), death of disease (p = 0.002), PR percentage (p = 0.002), and HER-2 expression (p = 0.018). Immunohistochemical nuclear localization of ß-Catenin was detected in 7.1% of the cohort. The combination of p53 and nuclear ß-Catenin expressions was not significantly predictive of disease-free or overall survival. CONCLUSION: The results of this study are useful for management of endometrial cancer in patients with DNA mismatch repair, abnormal p53 expression, or nuclear localization of ß-Catenin.
Asunto(s)
Carcinoma Endometrioide , Neoplasias Endometriales , Carcinoma Endometrioide/patología , Neoplasias Endometriales/patología , Femenino , Humanos , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/metabolismo , Estudios Retrospectivos , Proteína p53 Supresora de Tumor , beta CateninaRESUMEN
Endometrial cancer (EC) rates are rising annually. Additional prediction markers need to be evaluated because only 10-20% of EC cases show an objective response to immune-checkpoint inhibitors (ICIs). Our previous methylomic study found that BHLHE22 is hypermethylated in EC tissues and can be detected using a Pap-smear sample. BHLHE22, a basic helix loop helix transcription factor family member, is known as a transcriptional repressor and is involved in cell differentiation. However, the role of BHLHE22 in EC remains poorly understood. Herein, we analyzed BHLHE22 expression in 54 paired cancer and normal endometrial tissue samples, and confirmed with databases (TCGA, GTEx, and human protein atlas). We found that BHLHE22 protein expression was significantly downregulated in EC compared with normal endometrium. High BHLHE22 expression was associated with microsatellite-instable subtype, endometrioid type, grade, and age. It showed a significant favorable survival. BHLHE22 overexpression inhibited the proliferation and migration of EC cells. Functional enrichment analysis showed that BHLHE22 was significantly associated with immune-related pathways. Furthermore, BHLHE22 was positively correlated with proinflammatory leukocyte infiltration and expression of chemokine genes in EC. In conclusion, BHLHE22 regulates immune-related pathways and modulates the immune microenvironment of EC.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Neoplasias Endometriales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Quimiocinas/metabolismo , Neoplasias Endometriales/metabolismo , Endometrio/metabolismo , Femenino , Humanos , Microambiente TumoralRESUMEN
BACKGROUND: Approximately 25% of patients with early-stage breast cancer experience cancer progression throughout the disease course. Alterations in TMEM240 in breast cancer were identified and investigated to monitor treatment response and disease progression. METHODS: Circulating methylated TMEM240 in the plasma of breast cancer patients was used to monitor treatment response and disease progression. The Cancer Genome Atlas (TCGA) data in Western countries and Illumina methylation arrays in Taiwanese breast cancer patients were used to identify novel hypermethylated CpG sites and genes related to poor hormone therapy response. Quantitative methylation-specific PCR (QMSP), real-time reverse transcription PCR, and immunohistochemical analyses were performed to measure DNA methylation and mRNA and protein expression levels in 394 samples from Taiwanese and Korean breast cancer patients. TMEM240 gene manipulation, viability, migration assays, RNA-seq, and MetaCore were performed to determine its biological functions and relationship to hormone drug treatment response in breast cancer cells. RESULTS: Aberrant methylated TMEM240 was identified in breast cancer patients with poor hormone therapy response using genome-wide methylation analysis in the Taiwan and TCGA breast cancer cohorts. A cell model showed that TMEM240, which is localized to the cell membrane and cytoplasm, represses breast cancer cell proliferation and migration and regulates the expression levels of enzymes involved in estrone and estradiol metabolism. TMEM240 protein expression was observed in normal breast tissues but was not detected in 88.2% (67/76) of breast tumors and in 90.0% (9/10) of metastatic tumors from breast cancer patients. QMSP revealed that in 54.5% (55/101) of Taiwanese breast cancer patients, the methylation level of TMEM240 was at least twofold higher in tumor tissues than in matched normal breast tissues. Patients with hypermethylation of TMEM240 had poor 10-year overall survival (p = 0.003) and poor treatment response, especially hormone therapy response (p < 0.001). Circulating methylated TMEM240 dramatically and gradually decreased and then diminished in patients without disease progression, whereas it returned and its levels in plasma rose again in patients with disease progression. Prediction of disease progression based on circulating methylated TMEM240 was found to have 87.5% sensitivity, 93.1% specificity, and 90.2% accuracy. CONCLUSIONS: Hypermethylation of TMEM240 is a potential biomarker for treatment response and disease progression monitoring in breast cancer.
Asunto(s)
Antineoplásicos Hormonales , Neoplasias de la Mama , Metilación de ADN , Proteínas de la Membrana , Antineoplásicos Hormonales/uso terapéutico , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Neoplasias de la Mama/sangre , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Islas de CpG , Progresión de la Enfermedad , Femenino , Hormonas , Humanos , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/sangre , Proteínas de la Membrana/genética , Valor Predictivo de las PruebasRESUMEN
Adenomyosis is linked to dysmenorrhea and infertility. The pathogenesis of adenomyosis remains unclear, and little is known of the genetic and epigenetic changes in the eutopic endometrium in adenomyosis, which may predispose patients to the invasion and migration of endometrial tissues into the myometrium. Transcriptome studies have identified genes related to various cell behaviors but no targets for therapeutic intervention. The epigenetics of the eutopic endometrium in adenomyosis have rarely been investigated. Endometrial tissue was obtained from premenopausal women with (n = 32) or without adenomyosis (n = 17) who underwent hysterectomy aged 34-57 years at a tertiary hospital. The methylome and transcriptome were assessed by using a Methylation 450 K BeadChip array and Affymetrix expression microarray. Protein expression was examined by immunohistochemistry. Differential methylation analysis revealed 53 lowly methylated genes and 176 highly methylated genes with consistent gene expression in adenomyosis, including three genes encoding potassium ion channels. High expression of KCNK9 in the eutopic and ectopic endometria in patients with adenomyosis but not in normal controls was observed. Hormone-free, antibody-based KCNK9 targeting is a potential therapeutic strategy for adenomyosis-related dysmenorrhea, menorrhagia, and infertility.
Asunto(s)
Adenomiosis , Endometriosis , Infertilidad , Canales de Potasio de Dominio Poro en Tándem , Adenomiosis/genética , Adenomiosis/metabolismo , Adenomiosis/patología , Dismenorrea/genética , Endometriosis/patología , Endometrio/metabolismo , Epigenómica , Femenino , Humanos , Infertilidad/metabolismo , Canales de Potasio/metabolismo , Canales de Potasio de Dominio Poro en Tándem/metabolismoRESUMEN
Nerve growth factor (NGF) contributes to the progression of malignancy. However, the functional role and regulatory mechanisms of NGF in the development of neuroendocrine prostate cancer (NEPC) are unclear. Here, we show that an androgen-deprivation therapy (ADT)-stimulated transcription factor, ZBTB46, upregulated NGF via ZBTB46 mediated-transcriptional activation of NGF. NGF regulates NEPC differentiation by physically interacting with a G-protein-coupled receptor, cholinergic receptor muscarinic 4 (CHRM4), after ADT. Pharmacologic NGF blockade and NGF knockdown markedly inhibited CHRM4-mediated NEPC differentiation and AKT-MYCN signaling activation. CHRM4 stimulation was associated with ADT resistance and was significantly correlated with increased NGF in high-grade and small-cell neuroendocrine prostate cancer (SCNC) patient samples. Our results reveal a role of the NGF in the development of NEPC that is linked to ZBTB46 upregulation and CHRM4 accumulation. Our study provides evidence that the NGF-CHRM4 axis has potential to be considered as a therapeutic target to impair NEPC progression.
Asunto(s)
Adenocarcinoma/metabolismo , Carcinoma Neuroendocrino/etiología , Factor de Crecimiento Nervioso/metabolismo , Neoplasias de la Próstata/metabolismo , Factores de Transcripción/metabolismo , Adenocarcinoma/tratamiento farmacológico , Antagonistas de Andrógenos/efectos adversos , Carcinoma Neuroendocrino/metabolismo , Carcinoma Neuroendocrino/patología , Estudios de Casos y Controles , Resistencia a Antineoplásicos , Humanos , Masculino , Células PC-3 , Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Receptor Muscarínico M4/metabolismoRESUMEN
BACKGROUND: Patients with ovarian clear cell carcinoma (OCCC) have a poor prognosis because they show low sensitivity to platinum-based chemotherapy. New treatments for refractory OCCC are urgently needed. CASE PRESENTATION: We present a patient with refractory OCCC in whom conventional chemotherapy failed. Cachexia was induced by the disseminating recurrent tumors. Tumor tissue staining and genomic analysis revealed PD-L1 negativity, a low tumor burden, stable microsatellite instability, and two mutations in ARID1A. The patient was administered pembrolizumab combined with bevacizumab triweekly. Her serum CA-125 level decreased dramatically after the first cycle. A computerized tomography scan showed marked regression of the recurrent masses after 3 cycles, and the patient reached complete remission after 9 cycles. She showed good recovery from cachexia. We observed no marked side effects except for mild polyarthritis of the small joints. CONCLUSIONS: The therapeutic effect of checkpoint inhibitors combined with angiogenesis inhibitors is very promising in our patient with OCCC. Further clinical trials of tumors including ARID1A mutations are warranted.
Asunto(s)
Adenocarcinoma de Células Claras/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Bevacizumab/uso terapéutico , Proteínas de Unión al ADN/genética , Neoplasias Ováricas/tratamiento farmacológico , Factores de Transcripción/genética , Adenocarcinoma de Células Claras/patología , Anticuerpos Monoclonales Humanizados/farmacología , Bevacizumab/farmacología , Femenino , Humanos , Mutación , Neoplasias Ováricas/patologíaRESUMEN
BACKGROUND: Gene silencing by aberrant DNA methylation of promoter regions remains the most dominant phenomenon occurring during tumorigenesis. Improving the early diagnosis, prognosis, and recurrence prediction of colorectal cancer using noninvasive aberrant DNA methylation biomarkers has encouraging potential. The aim of this study is to characterize the DNA methylation of the promoter region of TMEM240, as well as gene expression and its effect on cell biological functions and its applications in early detection and outcome prediction. RESULTS: Highly methylated CpG sites were identified in the TMEM240 gene by Illumina methylation 450K arrays in 26 Taiwanese patient paired samples and 38 paired samples from The Cancer Genome Atlas (TCGA) colorectal cancer dataset. Transient transfection and knockdown of TMEM240 were performed to demonstrate the role of TMEM240 in colorectal cancer cells. The data showed that TMEM240 could lead to G1 cell cycle arrest, repress cancer cell proliferation, and inhibit cancer cell migration. The quantitative methylation-specific real-time polymerase chain reaction (PCR) results revealed that 87.8% (480 of 547) of the colorectal cancer tumors had hypermethylated TMEM240, and this was also found in benign tubular adenomas (55.6%). Circulating cell-free methylated TMEM240 was detected in 13 of 25 (52.0%) Taiwanese colorectal cancer patients but in fewer (28.6%) healthy controls. In 72.0% (85/118) of tissue samples, TMEM240 mRNA expression was lower in Taiwanese CRC tumor tissues than in normal colorectal tissues according to real-time reverse transcription PCR results, and this was also found in benign tubular adenomas (44.4%). The TMEM240 protein was analyzed in South Korean and Chinese CRC patient samples using immunohistochemistry. The results exhibited low protein expression in 91.7% (100/109) of tumors and 75.0% (24/32) of metastatic tumors but exhibited high expression in 75.0% (6/8) of normal colon tissues. Multivariate Cox proportional hazards regression analysis found that mRNA expression of TMEM240 was significantly associated with overall, cancer-specific, and recurrence-free survival (p = 0.012, 0.007, and 0.022, respectively). CONCLUSIONS: Alterations in TMEM240 are commonly found in Western and Asian populations and can potentially be used for early prediction and as poor prognosis and early-recurrence biomarkers in colorectal cancer.
Asunto(s)
Neoplasias Colorrectales/genética , Metilación de ADN , Proteínas de la Membrana/genética , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Movimiento Celular , Proliferación Celular , China , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Puntos de Control de la Fase G1 del Ciclo Celular , Humanos , Masculino , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/fisiología , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Pronóstico , ARN Mensajero/metabolismo , República de Corea , TaiwánRESUMEN
BACKGROUND: Endometrial cancer is a common gynecologic cancer. Noninvasive molecular biomarkers for triage of high-risk patients for invasive procedures are needed. Based on the success of cytological Pap smear screening, cervical scrapings are a good source of DNA for molecular testing. In addition to genetic lesions, DNA methylation is a promising biomarker. We assessed the usefulness of combining genetic and epigenetic biomarkers from cervical scrapings to detect endometrial carcinomas. METHODS: We performed a retrospective case-control study of 96 consecutive cervical scrapings from patients with abnormal uterine bleeding who underwent surgery for diagnostic evaluation. Thirty and 16 cases were diagnosed with type I and type II endometrial cancers, respectively. The remaining non-cancer cases included normal endometrium (n = 12), benign uterine lesions (n = 20), and endometrial hyperplasia (n = 18). Quantitative methylation-specific PCR and mass spectrometry were used for DNA methylation and genetic mutation analysis. Logistic regression was used to evaluate the clinical performance of these candidate biomarkers. RESULTS: We tested the effectiveness of the methylation status of four genes (BHLHE22, CDO1, TBX5, and HAND2) in endometrial cancer detection. The area under the receiver operating characteristic curves ranged from 0.703 to 0.878, and panels of hypermethylated BHLHE22/CDO1/HAND2 (87.0% sensitivity and 86.0% specificity) and BHLHE22/CDO1/TBX5 (89.1% sensitivity and 80.0% specificity) showed significant differences and could distinguish benign from malignant endometrial lesions. The sensitivity and specificity in endometrial cancer detection for BHLHE22/CDO1 were 84.8% and 88.0%, respectively. Both type I and II endometrial carcinomas could be detected using a BHLHE22/CDO1-based methylation profile, suggesting that they may have common epigenomes. Moreover, PTEN and TP53 mutations were found in 63.3% of type I and 93.6% of type II endometrial cancers. Unexpectedly, PTEN and TP53 mutations were commonly found in cervical scrapings of the normal endometrium (25% and 33.3%, respectively) and in cases with benign uterine lesions (10% and 50%, respectively). Finally, combinations of any one mutation of PTEN and TP53 mutations had a sensitivity of 91.3%, but a specificity of only 42.0%. CONCLUSIONS: Adding PTEN/TP53 mutation testing to BHLHE22/CDO1-based methylation testing did not improve the detection of endometrial cancer.
Asunto(s)
Biomarcadores de Tumor/genética , Metilación de ADN , Hiperplasia Endometrial/diagnóstico , Neoplasias Endometriales/diagnóstico , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Dilatación y Legrado Uterino , Hiperplasia Endometrial/patología , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Epigénesis Genética , Femenino , Humanos , Modelos Logísticos , Espectrometría de Masas , Persona de Mediana Edad , Estadificación de Neoplasias , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
As one of the deadliest and most common malignancies in the world, gastric cancer (GC) represents a serious health threat. Despite recent advances in the field, the prognosis of patients with metastatic GC remains poor. In this study, we aimed to investigate the clinical impact of the alpha subunit of the nuclear structural protein thymopoietin (TMPO-α) in GC. The expression of TMPO-α in seven gastric cell lines was detected by immunoblotting. The expression level of TMPO-α levels in gastric tissues collected from 145 GC patients was examined by immunohistochemistry. The correlations between TMPO-α expression level and clinicopathologic parameters, as well as the association of TMPO-α expression with overall survival, were assessed. Immunohistochemistry showed that the expression of TMPO-α was significantly higher in GC tissues and cells in comparison with non-tumor tissues and cells. Furthermore, the overexpression of TMPO-α in gastric tissues (56%) was positively associated with Lauren classification (P = 0.0159), nodal status (P = 0.0265), distant metastasis (P < 0.0001), stage (P = 0.0367), and degree of differentiation (P = 0.0009). Patients with high TMPO-α levels had a significantly poorer overall survival than those with low levels (P = 0.001). Multivariate Cox regression analysis also indicated that TMPO-α was an independent prognostic marker for GC (P = 0.045). In addition, studies conducted in GC cells indicated that knockdown of TMPO-α suppressed cell proliferation and invasion. These findings indicate that TMPO-α overexpression can predict clinicopathologic features and the outcome of patients with GC.
RESUMEN
Ovarian high-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy. Prevailing evidences suggest that drug resistance and recurrence of ovarian HGSC are caused by the presence of cancer stem cells. Therefore, targeting cancer stems is appealing, however, all attempts to date, have failed. To circumvent this limit, we analyzed differential transcriptomes at early differentiation of ovarian HGSC stem cells and identified the developmental transcription factor GATA3 as highly expressed in stem, compared to progenitor cells. GATA3 expression associates with poor prognosis of ovarian HGSC patients, and was found to recruit the histone H3, lysine 27 (H3K27) demethylase, UTX, activate stemness markers, and promote stem-like phenotypes in ovarian HGSC cell lines. Targeting UTX by its inhibitor, GSKJ4, impeded GATA3-driven stemness phenotypes, and enhanced apoptosis of GATA3-expressing cancer cells. Combinations of gemcitabine or paclitaxel with GSKJ4, resulted in a synergistic cytotoxic effect. Our findings provide evidence for a new role for GATA3 in ovarian HGSC stemness, and demonstrate that GATA3 may serve as a biomarker for precision epigenetic therapy in the future.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factor de Transcripción GATA3/efectos de los fármacos , Factor de Transcripción GATA3/fisiología , Células Madre Neoplásicas/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Fosfatasa Alcalina/metabolismo , Antígenos CD/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biomarcadores de Tumor/metabolismo , Cadherinas/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Linaje de la Célula , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Factor de Transcripción GATA3/metabolismo , Histona Demetilasas/metabolismo , Humanos , Células Madre Neoplásicas/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Ováricas/metabolismo , Paclitaxel/administración & dosificación , Pronóstico , Unión Proteica , Esferoides Celulares/enzimología , Esferoides Celulares/metabolismo , GemcitabinaRESUMEN
Precision medicine requires markers for therapeutic guidance. The purpose of this study was to determine whether epithelial ovarian cancer (EOC) epigenetics can lead to the identification of biomarkers for precision medicine. Through integrative methylomics, we discovered and validated the epigenetic signature of NEFH and HS3ST2 as an independent prognostic factor for type II EOC in our dataset (n = 84), and two independent methylomics datasets (total n = 467). Integrated transcriptomics dataset (n = 1147) and tissue microarrays (n = 54) of HS3ST2 also related to high-methylation statuses and the EOC prognosis. Mechanistic explorations of HS3ST2 have assessed responses to oncogenic stimulations such as IL-6, EGF, and FGF2 in cancer cells. The combination of HS3ST2 and various oncogenic ligands also confers the worse outcome. 3-O-sulfation of heparan sulfate by HS3ST2 makes ovarian cancer cells intrinsically sensitive to oncogenic signals, which sheds new light on the application of HS3ST2 as a companion diagnostic for targeted therapy using kinase inhibitors or therapeutic antibodies.
Asunto(s)
Carcinogénesis/genética , Epigénesis Genética/genética , Heparitina Sulfato/genética , Neoplasias Ováricas/genética , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Metilación de ADN/genética , Epigenómica/métodos , Femenino , Humanos , Persona de Mediana Edad , Proteínas de Neurofilamentos/genética , Oncogenes/genética , Neoplasias Ováricas/patología , Pronóstico , Transcriptoma/genética , Adulto JovenRESUMEN
Mucinous type of epithelial ovarian cancer (MuOC) is a unique subtype with a poor survival outcome in recurrent and advanced stages. The role of type-specific epigenomics and its clinical significance remains uncertain. We analyzed the methylomic profiles of 6 benign mucinous adenomas, 24 MuOCs, 103 serous type of epithelial ovarian cancers (SeOCs) and 337 nonepithelial ovarian cancers. MuOC and SeOC exhibited distinct DNA methylation profiles comprising 101 genes, 81 of which exhibited low methylation in MuOC and were associated with the response to glucocorticoid, ATP hydrolysis-coupled proton transport, proteolysis involved in the cellular protein catabolic process and ion transmembrane transport. Hierarchical clustering analysis showed that the profiles of MuOC were similar to colorectal adenocarcinoma and stomach adenocarcinoma. Genetic interaction network analysis of differentially methylated genes in MuOC showed a dominant network module is the proteasome subunit beta (PSMB) family. Combined functional module and methylation analysis identified PSMB8 as a candidate marker for MuOC. Immunohistochemical staining of PSMB8 used to validate in 94 samples of ovarian tumors (mucinous adenoma, MuOC or SeOC) and 62 samples of gastrointestinal cancer. PSMB8 was commonly expressed in MuOC and gastrointestinal cancer samples, predominantly as strong cytoplasmic and occasionally weak nuclei staining, but was not expressed in SeOC samples. Carfilzomib, a second-generation proteasome inhibitor, suppressed MuOC cell growth in vitro. This study unveiled a mucinous-type-specific methylation profile and suggests the potential use of a proteasome inhibitor to treat MuOC.
Asunto(s)
Adenocarcinoma Mucinoso/genética , Metilación de ADN , Oligopéptidos/farmacología , Neoplasias Ováricas/genética , Complejo de la Endopetidasa Proteasomal/genética , Inhibidores de Proteasoma/farmacología , Adenocarcinoma Mucinoso/tratamiento farmacológico , Adenocarcinoma Mucinoso/metabolismo , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Análisis por Conglomerados , Cistoadenoma Mucinoso/tratamiento farmacológico , Cistoadenoma Mucinoso/genética , Cistoadenoma Mucinoso/metabolismo , Epigenómica/métodos , Femenino , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismoRESUMEN
BACKGROUND/AIM: High-mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that is expressed in many human neoplasms. Oral squamous cell carcinoma (OSCC) is one of the leading cancers in the world, particularly in Southeast Asia. In this study, the expression level of HMGA2 was determined on tissue microarray of OSCC and its correlation with prognosis of patients was studied. MATERIALS AND METHODS: Immunohistochemistry of HMGA2 was analyzed on resection samples from 148 patients with OSCC. The expression level of HMGA2 was determined by ImmunoRatio. RESULTS: High expression of HMGA2 in OSCC was found to be associated with tumor recurrence (p=0.026). Cox model analysis revealed that high expression of HMGA2 was significantly associated with poor survival in patients with OSCC. The Kaplan-Meier analysis also showed decreased survival in patients with high HMGA2 expression. By combining HMGA2 immunostaining and clinicopathological characteristics as analyzing factors, high HMGA2 expression was specifically correlated with poor survival in patients with perineural invasion and lymph node metastasis of OSCC. Additionally, high expression of HMGA2 was found to be a tumor-stage independent prognostic factor associated with high incidence of tumor recurrence and shortened recurrence-free survival. CONCLUSION: HMGA2 is not only a biomarker for predicting patients with tumor recurrence and poor survival, but when combined with clinicopathological factors, can categorize patients into different risk groups for better clinical management of OSCC.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/mortalidad , Proteína HMGA2/metabolismo , Neoplasias de la Boca/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundario , Femenino , Humanos , Técnicas para Inmunoenzimas , Metástasis Linfática , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Clasificación del Tumor , Invasividad Neoplásica , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Increased expression of DEF6 is correlated with the malignant behavior of various cancers. Both DEF6 and p16 contribute to the regulation of cell cycle progression, and p53 plays important role in the cell cycle checkpoints. This study was designed to elucidate the prognostic significance of DEF6, p53 and p16 immunoexpressions in different histology subtypes of ovarian carcinoma. METHODS: Immunohistochemistry results of DEF6, p53 and p16 on ovarian carcinoma were compared with histology subtypes, clinical data, overall survival (OS) and disease-free survival (DFS) by Cox regression and Kaplan-Meier analysis. RESULTS: We studied 180 cases of ovarian carcinomas (75 high-grade serous, 41 clear cell, 36 mucinous and 28 endometrioid), including 109 FIGO stage I-II cases and 71 FIGO stage III-IV cases. Ovarian carcinomas positive for both DEF6 and p16 expression were associated with the worst OS (P = 0.027) and DFS (P = 0.023), whereas those negative for both DEF6 and p16 had the best OS and DFS. Aberrant p53 expression combined with positive DEF6 was associated with worst OS (P = 0.031) and DFS (P = 0.028). Kaplan-Meier analysis showed that significantly shorter survival rates were seen in patients with high expressions of DEF6 (P = 0.008) and p16 (P = 0.022). Patients with aberrant p53 expression in high-grade serous carcinoma (P = 0.012) and patients with high DEF6 expression in clear cell carcinoma (P = 0.001) were also associated with shorter overall survival. In univariate analysis, FIGO stage, DEF6 and p16 were associated with poor prognosis. DEF6 expression was the only independent prognostic factor correlated with shorted OS (HR 2.115; P = 0.025) and DFS (HR 2.248; P = 0.016) upon multivariate analysis. CONCLUSIONS: DEF6 expression may serve as an independent prognostic factor, and interacted positively with p16 toward high tumor stage and shorter survival.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Proteínas de Unión al ADN/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Ováricas/diagnóstico , Proteína p53 Supresora de Tumor/metabolismo , Adenocarcinoma de Células Claras/diagnóstico , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/mortalidad , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/mortalidad , Línea Celular Tumoral , Estudios de Cohortes , Cistadenoma Seroso/diagnóstico , Cistadenoma Seroso/metabolismo , Cistadenoma Seroso/mortalidad , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Análisis Multivariante , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/mortalidad , PronósticoRESUMEN
The aim of the present study was to report a rare case of single-clone, immunoglobulin heavy chain (IgH)-rearranged mucosa-associated lymphoid tissue (MALT) lymphoma in the conjunctiva, with nasal cavity dissemination through the nasolacrimal duct. A 24-year-old female was diagnosed with MALT lymphoma of the nasal cavity at the Department of Otolaryngology, Wan Fang Medical Center, Taipei Medical University (Tapei, Taiwan) in October 2008. A biopsy of the relapsing conjunctival lesion revealed a MALT lymphoma by pathological staining, while a single-clone, IgH-rearranged tumor lesion in the nasal cavity and conjunctiva was confirmed using continuous sinus computed tomography scans and polymerase chain reaction. Tumor lesions were negative for Helicobacter pylori and Chlamydia infection, but exhibited bilateral neck lymph node dissemination. A combination of radiation therapy (a total dosage of 46.8 Gray, in two phases covering the left lacrimal sac, nasal cavity and bilateral neck region) and topical ciprofloxacin plus steroid (0.3% ciprofloxacin 4 times a day and betamethasone eye ointment before sleep for 1 month) was provided as an effective therapeutic strategy, and no recurrence was found in the next 3 years. The nasolacrimal duct serves as a channel for conjunctival tumor spreading and is easily neglected. IgH-involved translocation in MALT lymphoma is a factor in the progression of the disease, and aggressive combination therapy is essential for a high-risk, disseminated IgH-rearranged MALT lymphoma.
RESUMEN
OBJECTIVES: Despite considerable interest in the Nuclear factor-erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap1), p16 and epithelial cadherin (E-cadherin) activation in carcinoma progression, contradictory results regarding association of Nrf2/Keap1/E-cadherin and p16 expression with clinico-pathological features and prognosis have been reported. The predictive value of these markers in ovarian carcinoma is unknown. METHODS/MATERIALS: In this retrospective study, 108 cases were evaluated immunohistochemically with antibodies to Nrf2, Keap1, estrogen receptor (ER), p16 and E-cadherin. The results were compared with histological and clinical data, disease-free survival (DFS) and overall survival (OS). RESULTS: A cohort of 108 ovarian carcinomas (47 serous, 23 mucinous, 13 endometrioid and 25 clear cell), including 68 FIGO stage I-II cases and 40 FIGO stage III-IV cases was studied. The age of patients (P=0.005), FIGO stage (P<0.001), immunohistochemical expression of Keap1 (P<0.000), E-cadherin (P=0.045), p53 (P=0.003), p16 (P<0.001) and ER (P=0.004) were significant factors between different histological subtypes. Patients with serous carcinoma were older in age, presented with more advanced stage disease, worst prognosis, highest Keap1 expression and least percentage of E-cadherin immunoreactivity. In univariate analysis, FIGO staging (P=0.000 for DFS; P=0.000 for OS), Nrf2 (P=0.010 for DFS; P=0.001 for OS), and p16 (P=0.004 for DFS; P=0.019 for OS) were associated with worse prognosis. After multivariate analysis, FIGO staging and Nrf2 remained significance prognostic factors. CONCLUSIONS: There were differences in the expression of Nrf2, Keap1, p16 and E-cadherin between different ovarian carcinoma subtypes. In multivariate analysis, FIGO stage and Nrf2 expression were associated with poorer DFS and OS.
Asunto(s)
Biomarcadores de Tumor/análisis , Cadherinas/análisis , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , Péptidos y Proteínas de Señalización Intracelular/análisis , Factor 2 Relacionado con NF-E2/análisis , Neoplasias Glandulares y Epiteliales/química , Neoplasias Ováricas/química , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antígenos CD , Carcinoma Epitelial de Ovario , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Proteína 1 Asociada A ECH Tipo Kelch , Modelos Logísticos , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Glandulares y Epiteliales/terapia , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Análisis de Matrices Tisulares , Resultado del TratamientoRESUMEN
BACKGROUND: Gastroenterology is a beneficial treatment of morbidly obese type 2 diabetes mellitus (T2DM). We aimed to identify the predictors for the treatment of T2DM obese patients. METHODS: A retrospective study consisting of 531 patients undergoing laparoscopic gastric banding (LGB), laparoscopic mini-gastric bypass (LMGB) and laparoscopic sleeve gastrectomy (LSG) from January 2004 to May 2007 was performed. Patients with preoperative fasting serum glucose concentration of more than 126 mg/dl were diagnosed as T2DM. A postoperatively fasting serum glucose level of less than 110 mg/dl was considered to be remission of T2DM. RESULTS: Of the 531 patients, 62 (11.6%) were diagnosed as T2DM, including 23 men and 39 women, with a mean age of 31.8 ± 9.2 years, and a mean body mass index (BMI) of 40.0 kg/m(2). The mean glucose at 3, 6, and 12 months after surgery were 100.1 mg/dl, 95.1 mg/dl and 91.8 mg/dl, respectively. The mean body weight loss one year after surgery was 9.4% for LGB, 31.4% for LSG and 37.1% for LMGB, respectively. Among these operation methods (LGB, LMGB and LSG), the BMI, body weight, waist circumference, serum lipid profile and serum factors associated with glucose metabolism were significantly different during the one-year postoperative follow-up. Remission rate of T2DM was achieved in 84.8%, 58.8% and 58.3% of patients for LMGB, LGB and LSG, respectively. The best operative method for the remission of T2DM was LMGB. Using an artificial neural network (ANN) data mining technique, waist circumference, operative methods and C-peptide were significantly predictors for the remission of T2 DM. CONCLUSION: One year after gastrointestinal surgery, improvement of serum lipid profiles and serum data related to glucose metabolism in the different operative methods were noticed. LMGB seems to be the most effective procedure for the reduction of serum glucose levels compared with LAGB and LSG.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Tipo 2/cirugía , Derivación Gástrica , Gastroplastia , Laparoscopía , Obesidad Mórbida/cirugía , Adolescente , Adulto , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad Mórbida/sangre , Obesidad Mórbida/complicaciones , Inducción de Remisión , Estudios Retrospectivos , Pérdida de PesoRESUMEN
BACKGROUND/AIMS: Bariatric surgery is the only proven method that produces sustained weight loss. We aimed to investigate the Gastrointestinal Quality of Life Index (GIQLI) differences between obese patients following laparoscopic mini-gastric bypass (LMGB), laparoscopic adjustable gastric banding (LAGB) and laparoscopic sleeve gastrectomy (LSG) in this study. METHODOLOGY: From December 2005 to December 2007, we enrolled 152 patients who received bariatric surgery, including 41 men and 111 women, mean age 32.6±9.4 years and mean BMI 37.4±7.9kg/m2 (range 32.0-64.9). Clinical characteristics and quality of life were analyzed. RESULTS: One year after bariatric surgery, the mean general score of GIQLI improved significantly (p=0.000). All patients had improvement in three domains of the questionnaire (social function, physical status and emotional status) but not in gastrointestinal symptoms. The preoperative general score was 105.9±15.4 points in LMGB group, 110.9±14.8 points in LAGB group and 99.0±19.8 points in LSG group, respectively. Despite a significant difference between three groups regarding preoperative GIQLI scores (p=0.001), the 1-year results failed to show any significant difference in a comparison of postoperative GIQLI scores (p=0.082). CONCLUSIONS: In conclusion, our study has demonstrated significant improvement in quality of life 1-year after laparoscopic bariatric surgery. The improvement of GIQLI scores in three domains of social function, physical status and emotional status can be offered to obese patients before surgery.