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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.
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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.
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Carcinoma Endometrioide , Neoplasias do Endométrio , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Estudos Retrospectivos , Proteína Supressora de Tumor p53 , beta CateninaRESUMO
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.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos , Neoplasias do Endométrio , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Quimiocinas/metabolismo , Neoplasias do Endométrio/metabolismo , Endométrio/metabolismo , Feminino , Humanos , Microambiente TumoralRESUMO
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.
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Antineoplásicos Hormonais , Neoplasias da Mama , Metilação de DNA , Proteínas de Membrana , Antineoplásicos Hormonais/uso terapêutico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Ilhas de CpG , Progressão da Doença , Feminino , Hormônios , Humanos , Proteínas de Membrana/biossíntese , Proteínas de Membrana/sangue , Proteínas de Membrana/genética , Valor Preditivo dos TestesRESUMO
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.
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Adenomiose , Endometriose , Infertilidade , Canais de Potássio de Domínios Poros em Tandem , Adenomiose/genética , Adenomiose/metabolismo , Adenomiose/patologia , Dismenorreia/genética , Endometriose/patologia , Endométrio/metabolismo , Epigenômica , Feminino , Humanos , Infertilidade/metabolismo , Canais de Potássio/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismoRESUMO
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.
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Adenocarcinoma/metabolismo , Carcinoma Neuroendócrino/etiologia , Fator de Crescimento Neural/metabolismo , Neoplasias da Próstata/metabolismo , Fatores de Transcrição/metabolismo , Adenocarcinoma/tratamento farmacológico , Antagonistas de Androgênios/efeitos adversos , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Estudos de Casos e Controles , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Células PC-3 , Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Receptor Muscarínico M4/metabolismoRESUMO
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.
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Adenocarcinoma de Células Claras/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Bevacizumab/uso terapêutico , Proteínas de Ligação a DNA/genética , Neoplasias Ovarianas/tratamento farmacológico , Fatores de Transcrição/genética , Adenocarcinoma de Células Claras/patologia , Anticorpos Monoclonais Humanizados/farmacologia , Bevacizumab/farmacologia , Feminino , Humanos , Mutação , Neoplasias Ovarianas/patologiaRESUMO
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.
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Neoplasias Colorretais/genética , Metilação de DNA , Proteínas de Membrana/genética , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Movimento Celular , Proliferação de Células , China , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Pontos de Checagem da Fase G1 do Ciclo Celular , Humanos , Masculino , Proteínas de Membrana/metabolismo , Proteínas de Membrana/fisiologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Prognóstico , RNA Mensageiro/metabolismo , República da Coreia , TaiwanRESUMO
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.
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Biomarcadores Tumorais/genética , Metilação de DNA , Hiperplasia Endometrial/diagnóstico , Neoplasias do Endométrio/diagnóstico , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Dilatação e Curetagem , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Epigênese Genética , Feminino , Humanos , Modelos Logísticos , Espectrometria de Massas , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
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.
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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.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator de Transcrição GATA3/efeitos dos fármacos , Fator de Transcrição GATA3/fisiologia , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Fosfatase Alcalina/metabolismo , Antígenos CD/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Linhagem da Célula , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Fator de Transcrição GATA3/metabolismo , Histona Desmetilases/metabolismo , Humanos , Células-Tronco Neoplásicas/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/metabolismo , Paclitaxel/administração & dosagem , Prognóstico , Ligação Proteica , Esferoides Celulares/enzimologia , Esferoides Celulares/metabolismo , GencitabinaRESUMO
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.
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Carcinogênese/genética , Epigênese Genética/genética , Heparitina Sulfato/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Metilação de DNA/genética , Epigenômica/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/genética , Oncogenes/genética , Neoplasias Ovarianas/patologia , Prognóstico , Transcriptoma/genética , Adulto JovemRESUMO
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.
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Adenocarcinoma Mucinoso/genética , Metilação de DNA , Oligopeptídeos/farmacologia , Neoplasias Ovarianas/genética , Complexo de Endopeptidases do Proteassoma/genética , Inibidores de Proteassoma/farmacologia , Adenocarcinoma Mucinoso/tratamento farmacológico , Adenocarcinoma Mucinoso/metabolismo , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Análise por Conglomerados , Cistadenoma Mucinoso/tratamento farmacológico , Cistadenoma Mucinoso/genética , Cistadenoma Mucinoso/metabolismo , Epigenômica/métodos , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismoRESUMO
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.
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Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/mortalidade , Proteína HMGA2/metabolismo , Neoplasias Bucais/mortalidade , Recidiva Local de Neoplasia/mortalidade , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundário , Feminino , Humanos , Técnicas Imunoenzimáticas , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
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.
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Biomarcadores Tumorais/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/diagnóstico , Proteína Supressora de Tumor p53/metabolismo , Adenocarcinoma de Células Claras/diagnóstico , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/mortalidade , Linhagem Celular Tumoral , Estudos de Coortes , Cistadenoma Seroso/diagnóstico , Cistadenoma Seroso/metabolismo , Cistadenoma Seroso/mortalidade , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , PrognósticoRESUMO
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.
RESUMO
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.
Assuntos
Biomarcadores Tumorais/análise , Caderinas/análise , Inibidor p16 de Quinase Dependente de Ciclina/análise , Peptídeos e Proteínas de Sinalização Intracelular/análise , Fator 2 Relacionado a NF-E2/análise , Neoplasias Epiteliais e Glandulares/química , Neoplasias Ovarianas/química , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antígenos CD , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Proteína 1 Associada a ECH Semelhante a Kelch , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Epiteliais e Glandulares/terapia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Análise Serial de Tecidos , Resultado do TratamentoRESUMO
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.
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Glicemia/metabolismo , Diabetes Mellitus Tipo 2/cirurgia , Derivação Gástrica , Gastroplastia , Laparoscopia , Obesidade Mórbida/cirurgia , Adolescente , Adulto , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/sangue , Obesidade Mórbida/complicações , Indução de Remissão , Estudos Retrospectivos , Redução de PesoRESUMO
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.