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BACKGROUND: Endocrine therapy resistance in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) is a significant clinical challenge that poses several unmet needs in the management of the disease. This study aimed to investigate the prognostic value of c-MET-positive circulating tumor cells (cMET+ CTCs), ESR1/PIK3CA mutations, and cell-free DNA (cfDNA) concentrations in patients with hormone receptor-positive (HR+) metastatic breast cancer (mBC). METHODS: Ninety-seven patients with HR+ mBC were prospectively enrolled during standard treatment at Samsung Medical Center. CTCs were isolated from blood using GenoCTC® and EpCAM or c-MET CTC isolation kits. PIK3CA and ESR1 hotspot mutations were analyzed using droplet digital PCR. CfDNA concentrations were calculated using internal control copies from the ESR1 mutation test. Immunocytochemistry was performed to compare c-MET overexpression between primary and metastatic sites. RESULTS: The proportion of c-MET overexpression was significantly higher in metastatic sites than in primary sites (p = 0.00002). Survival analysis showed that c-MET+ CTC, cfDNA concentration, and ESR1 mutations were significantly associated with poor prognosis (p = 0.0026, 0.0021, and 0.0064, respectively) in HR+/HER2- mBC. By contrast, EpCAM-positive CTC (EpCAM+ CTC) and PIK3CA mutations were not associated with progression-free survival (PFS) in HR+/HER2- mBC. Multivariate analyses revealed that c-MET+ CTCs and cfDNA concentration were independent predictors of PFS in HR+/HER2- mBC. CONCLUSIONS: Monitoring c-MET+ CTC, rather than assessing c-MET expression in the primary BC site, could provide valuable information for predicting disease progression, as c-MET expression can change during treatment. The c-MET+ CTC count and cfDNA concentration could provide complementary information on disease progression in HR+ /HER2- mBC, highlighting the importance of integrated liquid biopsy.
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Neoplasias de la Mama , Ácidos Nucleicos Libres de Células , Células Neoplásicas Circulantes , Humanos , Femenino , Neoplasias de la Mama/patología , Células Neoplásicas Circulantes/patología , Ácidos Nucleicos Libres de Células/uso terapéutico , Pronóstico , Molécula de Adhesión Celular Epitelial/genética , Biomarcadores de Tumor/genética , Progresión de la Enfermedad , Fosfatidilinositol 3-Quinasa Clase I/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismoRESUMEN
Objectives: We evaluated whether the coronavirus disease 2019 (COVID-19) pandemic caused delays in the diagnosis and treatment of colorectal cancer (CRC) in Korea, where there have been no regional or hospital lockdowns during the pandemic period. Methods: Data on CRC patients (n=1,445) diagnosed in Gwangju Metropolitan City and Jeonnam Province between January 2019 and December 2021 were assessed. The stage at the time of CRC diagnosis, route to diagnosis, time to initial cancer treatment, and length of hospital admission were compared before and during the COVID-19 pandemic. Logistic regression was also performed to identify factors associated with the risk for diagnosis in an advanced stage. Results: No negative effects indicating a higher CRC stage at diagnosis or delayed treatment during the pandemic were observed. Instead, the risk for an advanced stage at diagnosis (TNM stage III/IV) decreased in CRC patients diagnosed during the pandemic (odds ratio, 0.768; 95% confidence interval, 0.647 to 0.911). No significant differences in the interval from diagnosis to operation or chemotherapy were observed. Conclusion: No negative effects on CRC diagnosis and treatment were found until the end of 2021, which may be related to the small magnitude of the COVID-19 epidemic, the absence of a lockdown policy in Korea, and the rebound in the number of diagnostic colonoscopy procedures in 2021.
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COVID-19 , Neoplasias Colorrectales , Humanos , COVID-19/epidemiología , Pandemias , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Control de Enfermedades Transmisibles , República de Corea/epidemiología , Detección Precoz del Cáncer , Prueba de COVID-19RESUMEN
BACKGROUND: A disputed rpoB mutation is a specific type of rpoB mutation that can cause low-level resistances to rifampin (RIF). Here, we aimed to assess the frequency and types of disputed rpoB mutations in Mycobacterium tuberculosis isolates from South Korea. METHODS: Between August 2009 and December 2015, 130 patients exhibited RIF resistance on the MTBDRplus assay at Asan Medical Center. Among these cases, we identified the strains with disputed rpoB mutation by rpoB sequencing analysis, as well as among the M. tuberculosis strains from the International Tuberculosis Research Center (ITRC). RESULTS: Among our cases, disputed rpoB mutations led to RIF resistance in at least 6.9% (9/130) of the strains that also exhibited RIF resistance on the MTBDRplus assay. Moreover, at the ITRC, sequencing of the rpoB gene of 170 strains with the rpoB mutation indicated that 23 strains (13.5%) had the disputed mutations. By combining the findings from the 32 strains from our center and the ITRC, we identified the type of disputed rpoB mutation as follows: CTG511CCG (L511P, n=8), GAC516TAC (D516Y, n=8), CTG533CCG (L533P, n=8), CAC526CTC (H526L, n=4), CAC526AAC (H526N, n=3), and ATG515GTG (M515V, n=1). CONCLUSION: Disputed rpoB mutations do not seem to be rare among the strains exhibiting RIF resistance in South Korea.
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BACKGROUND: The aim of this study was to evaluate whether stage at cancer diagnosis differed according to patient economic status. METHODS: A total of 10,528 patients with cancer of the stomach, colorectum, breast, or cervix, which are target organs of the Korean National Cancer Screening Program (NCSP; fully implemented in 2005) were extracted from population-based cancer registries. The patients were classified into four groups based on socioeconomic status (SES), as determined using their National Health Insurance (NHI) monthly premium at the time of cancer diagnosis. Cancer stage at diagnosis was defined as early (in situ/local) or late stage (regional/distant) based on the Surveillance, Epidemiology, and End Results (SEER) summary stage. Multivariable logistic regression analysis was performed to estimate the risk of non-local stage using age, residential area, and community deprivation index as covariates. RESULTS: The lowest SES subjects showed significantly higher risks of being diagnosed at a later stage for stomach, colorectal, and female breast cancer, but not for cervical cancer, compared with the highest SES subjects. The estimated ORs were 1.28 (95% CI, 1.10-1.49), 1.29 (95% CI, 1.03-1.61), and 1.35 (95% CI, 1.02-1.81) in the lowest SES subjects with stomach, colorectal, and breast cancer, respectively. CONCLUSIONS: In conclusion, later stage diagnoses of stomach, colon, and female breast cancer are still associated with SES in Korea in the era of the NCSP for the lower SES population.
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Disparidades en el Estado de Salud , Neoplasias/patología , Clase Social , Anciano , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Detección Precoz del Cáncer , Femenino , Humanos , Masculino , Persona de Mediana Edad , Programas Nacionales de Salud , Estadificación de Neoplasias , Neoplasias/diagnóstico , Sistema de Registros , República de Corea , Medición de Riesgo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patología , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/patologíaRESUMEN
Extensively drug-resistant tuberculosis (XDR-TB) is a serious worldwide problem. The REBA MTB-XDR (REBA-XDR) was recently developed in Korea to detect resistance to ofloxacin, kanamycin, and streptomycin. The aim of this study is to evaluate the diagnostic accuracy of the REBA-XDR. We prospectively enrolled 104 patients with acid-fast bacilli smear-positive specimens between July 2010 and January 2013. Performance characteristics were compared between REBA-XDR and conventional drug-susceptibility testing. The sensitivity values of REBA-XDR for detecting resistance to ofloxacin, kanamycin, and streptomycin were 66.7%, 90.9%, and 60.0%, and the specificity values were 93.3%, 93.5%, and 85.4%, respectively. The positive predictive values were 62.5%, 62.5%, and 40.9%, and the negative predictive values were 94.3%, 98.9%, and 92.7%, respectively. Accuracy was 89.4%, 93.3%, and 81.7%, respectively. REBA-XDR seems to be a useful kit for "ruling in" XDR-TB in intermediate-burden countries, and especially useful for detecting kanamycin resistance.
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Antibacterianos/farmacología , Tuberculosis Extensivamente Resistente a Drogas/tratamiento farmacológico , Genes MDR , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Adulto , Farmacorresistencia Bacteriana Múltiple , Tuberculosis Extensivamente Resistente a Drogas/diagnóstico , Femenino , Humanos , Isoniazida/farmacología , Kanamicina/farmacología , Masculino , Pruebas de Sensibilidad Microbiana/métodos , Persona de Mediana Edad , Ofloxacino/farmacología , Valor Predictivo de las Pruebas , República de Corea , Rifampin/farmacología , Esputo/microbiología , Estreptomicina/farmacologíaRESUMEN
We report the draft genome sequence of Lactobacillus sakei strain wikim 22, a Lactobacillus species isolated from kimchi in North Chungcheong Province, South Korea, having 155 contigs with 2,447 genes and an average G+C content of 40.61%.
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BACKGROUND: Despite many studies on endoplasmic reticulum (ER) stress in patients with various inflammatory diseases, there is scarce information on ER stress in patients with bronchial asthma. OBJECTIVE: In this study we aimed to elucidate the role of ER stress in the pathogenesis of bronchial asthma. METHODS: Using mice sensitized with ovalbumin (OVA) and LPS and challenged with OVA (OVA(LPS)-OVA mice), as well as mice sensitized and challenged with OVA (OVA-OVA mice), we investigated whether ER stress is involved in the pathogenesis of bronchial asthma. Moreover, we also determined the levels of ER stress markers in blood and bronchoalveolar lavage fluid from asthmatic patients. RESULTS: The OVA(LPS)-OVA mice showed that the expression of ER stress markers and the protein levels of unfolded protein response-related markers in lung tissue were significantly increased after OVA challenge. Moreover, we found that ER stress markers in PBMCs and bronchoalveolar lavage fluid from human asthmatic patients were dramatically increased compared with those from healthy control subjects. In OVA(LPS)-OVA mice 4-phenylbutyric acid (4-PBA), a chemical chaperone, significantly reduced the increases in ER stress, nuclear translocation of nuclear factor κB, inflammatory cytokine levels, dendritic cell infiltration, Toll-like receptor 4 expression, airway inflammation, and bronchial hyperresponsiveness, whereas it further enhanced the increase in IL-10 levels. Additionally, the established asthmatic features of OVA-OVA mice were substantially attenuated by 4-PBA administered after completion of OVA challenge. CONCLUSION: These results indicate that ER stress might be implicated in the pathogenesis of bronchial asthma at least in part through modulation of nuclear factor κB activation.
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Asma/inmunología , Estrés del Retículo Endoplásmico/inmunología , FN-kappa B/metabolismo , Animales , Asma/tratamiento farmacológico , Biomarcadores/metabolismo , Butilaminas/administración & dosificación , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/inmunología , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/inmunología , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Activación Transcripcional/efectos de los fármacos , Activación Transcripcional/inmunologíaRESUMEN
AIMS: Chromodomain helicase DNA-binding protein (CHD) is a regulator of the chromatin remodelling process. The aim was to determine the CHD1, CHD2, CHD3, CHD4, CHD7, CHD8 and CHD9 mutational status of mononucleotide repeats in gastric and colorectal cancers with microsatellite instability (MSI). METHODS AND RESULTS: The repeats were determined in 28 gastric cancers (GCs) with high MSI (MSI-H), 45 GCs with low MSI (MSI-L)/stable MSI (MSS), 35 colorectal cancers (CRCs) with MSI-H and 45 CRCs with MSI-L/MSS by single-strand conformation polymorphism analysis. CHD4 and CHD8 expression was also examined in GCs and CRCs by immunohistochemistry. CHD1, CHD2, CHD3, CHD4, CHD7, CHD8 and CHD9 mutations were found in five, 19, three, five, seven, 10 and seven cancers, respectively. They were detected in MSI-H cancers, but not in MSI-L/MSS cancers. Loss of CHD4 expression was observed in 56.4% of the GCs and 55.7% of the CRCs, and loss of CHD8 was observed in 35.7% of the GCs and 28.6% of the CRCs. The cancers with CHD4 and CHD8 mutations showed loss of CHD4 and CHD8 expression, respectively. CONCLUSIONS: Frameshift mutation and loss of expression of CHD genes are common in GCs and CRCs with MSI-H.These alterations might contribute to cancer pathogenesis by deregulating CHD-mediated chromatin remodelling.
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Neoplasias Colorrectales/genética , ADN Helicasas/genética , ADN Helicasas/metabolismo , Mutación del Sistema de Lectura , Regulación Neoplásica de la Expresión Génica , Neoplasias Gástricas/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , ADN de Neoplasias/metabolismo , Inestabilidad de Microsatélites , Repeticiones de Microsatélite , Polimorfismo Conformacional Retorcido-Simple , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaAsunto(s)
Neoplasias Colorrectales/genética , Proteínas de Homeodominio/genética , Neoplasias Gástricas/genética , Proteínas Supresoras de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Proteínas Wnt/genética , Adulto , Anciano , Análisis Mutacional de ADN , Enzima Desubiquitinante CYLD , Femenino , Mutación del Sistema de Lectura , Humanos , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Adulto JovenAsunto(s)
Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Carcinoma de Células Escamosas/metabolismo , Caspasas/metabolismo , Neoplasias Esofágicas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Anciano , Apoptosis , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/patología , Caspasa 6/metabolismo , Caspasa 9/metabolismo , Neoplasias Esofágicas/patología , Humanos , Persona de Mediana EdadRESUMEN
Coordinated protein phosphorylation and dephosphorylation are crucial in the regulation of cell signaling, and disruption of the coordination is known to play important roles in cancer development. Recent reports revealed that classical protein tyrosine phosphatase (PTP)-encoded genes are somatically mutated in human colorectal cancer. However, data on dual specificity phosphatase (DPTP) gene mutations in human cancers are lacking. By analyzing a public genomic database, we found that five DPTP genes, CDC14A, MTM1, MTMR3, SSH1, and SSH2, have mononucleotide repeats in their coding DNA sequences. To see whether these genes are mutated in cancers with microsatellite instability (MSI), we analyzed the mononucleotide repeats in 26 gastric cancers (GC) with MSI (MSI-H), 12 GC with low MSI (MSI-L), 45 GC with stable MSI (MSS), 33 colorectal cancers (CRC) with MSI-H, 14 CRC with MSI-L, and 45 CRC with MSS by single-strand conformation polymorphism (SSCP). We found CDC14A and MTMR3 mutations in five and one cancer (s), respectively. These mutations were detected in MSI-H cancers, but not in MSI-L or MSS cancers. The GC and CRC with MSI-H harbored the mutations in 15% and 6%, respectively. The CDC14A and MTMR3 mutations detected in the GC and CRC were deletion or duplication mutations of one base in the nucleotide repeats that would result in premature stops of the amino acid syntheses. Our data show that frameshift mutations of DPTP genes in MSI-H cancers occur at moderate frequencies. The data suggested that alterations in the CDC14A and MTMR3 genes may play a role in the development of GC and CRC with MSI-H by deregulating phosphatase functions possibly together with mutations of classical PTP genes.
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Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , ADN de Neoplasias/genética , Fosfatasas de Especificidad Dual/genética , Inestabilidad de Microsatélites , Repeticiones de Microsatélite , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/genética , Secuencia de Bases , Codón sin Sentido , Análisis Mutacional de ADN , Mutación del Sistema de Lectura , Humanos , Monoéster Fosfórico Hidrolasas/genética , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Proteínas Tirosina Fosfatasas , Proteínas Tirosina Fosfatasas no Receptoras/genética , Eliminación de SecuenciaRESUMEN
AIMS AND BACKGROUND: Microsatellite instability (MSI) in sporadic gastric cancer (GC) and colorectal cancer (CRC) causes frameshift mutations in gene sequences that contribute to cancer pathogenesis. Many mutations have already been identified in these two cancer types, but some are still undiscovered. METHODS: We analyzed seven genes (cell cycle control and DNA damage signaling/repair-related genes) with seven or more mononucleotide repeats in 30 GC samples with high MSI (MSI-H), 15 GC samples with low MSI (MSI-L), 45 GC samples that were microsatellite stable (MSS), 33 CRC samples with MSI-H, 15 CRC samples with MSI-L, and 45 CRC samples that were MSS. Single-strand conformation polymorphism (SSCP) and DNA sequencing were used for the analysis. RESULTS: We found somatic frameshit mutations of the KNTC1 (6.7% GC, 12.1% CRC), ZC3H13 (3.3% GC, 15.2% CRC), CENPH (6.7% GC), TOPBP1 (3.0% CRC), NDCO80 (3.0% CRC), RIF1 (6.7% GC), and NBS1 (3.3% GC, 3.0% CRC) genes in the cancers with MSI-H. Mutations were detected in MSI-H, but not in MSI-L or MSS samples. CONCLUSIONS: Novel frameshift mutations occurred in seven genes in GC and CRC with MSI-H. The results of our study suggest that the mutations might contribute to the development of GC and CRC with MSI by deregulation of the cell cycle and DNA damage signaling/repair.
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Proteínas de Ciclo Celular/genética , Ciclo Celular/genética , Neoplasias Colorrectales/genética , Daño del ADN/genética , Reparación del ADN/genética , Mutación del Sistema de Lectura , Inestabilidad de Microsatélites , Neoplasias Gástricas/genética , Pueblo Asiatico/genética , Proteínas Portadoras/genética , Proteínas Cromosómicas no Histona/genética , Neoplasias Colorrectales/patología , Proteínas del Citoesqueleto , Cartilla de ADN , ADN de Neoplasias/análisis , Proteínas de Unión al ADN/genética , Humanos , Proteínas Asociadas a Microtúbulos/genética , Proteínas Nucleares/genética , Polimorfismo Conformacional Retorcido-Simple , Proteínas de Unión al ARN , Análisis de Secuencia de ADN , Neoplasias Gástricas/patología , Proteínas de Unión a Telómeros/genéticaRESUMEN
AIMS: Activation of nuclear factor-kappa B (NF-kappaB) signalling is considered a crucial mechanism in the development of cancers. Caspase-associated recruitment domain 6 (CARD6) is a protein that activates NF-kappaB signalling evoked by RIP1, RIP2, Bcl-10 and MEKK. In this study, we analysed tissue expression of CARD6 protein in oesophageal squamous cell carcinoma (ESCC), gastric adenocarcinomas (GC) and colorectal adenocarcinomas (CRC). METHODS: We analysed the expression of CARD6 protein in 58 ESCC, 100 GC and 103 CRC patients' tissues by immunohistochemistry using a tissue microarray (TMA) approach. RESULTS: We found CARD6 immunostaining in cancer cells of ESCC (41/58; 70.7%), GC (45/100; 45.0%) and CRC (81/103; 78.6%). In the GC, intestinal-type GC (77.8%) showed higher expression of CARD6 than diffuse-type GC (20.0%) and mixed-type GC (50.0%). By contrast, corresponding normal epithelial cells of oesophagus (0%), stomach (8.0%) and colon (5.0%) displayed lower frequencies of CARD6 immunostaining. The CARD6 immunostaining was observed in nucleus/cytoplasm (ESCC) or cytoplasm (GC and CRC). The CARD6 expression was evident from an early TNM stage (stage I). CONCLUSION: The increased expression of CARD6 in ESCC, GC and CRC tissues compared to their corresponding normal cells suggested that neoexpression of CARD6 might be related to activation of NF-kappaB pathway in the cancers and might play a role in the development of most types of gastrointestinal cancers.
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Biomarcadores de Tumor/metabolismo , Proteínas Adaptadoras de Señalización CARD/metabolismo , Neoplasias Colorrectales/metabolismo , Neoplasias Esofágicas/metabolismo , FN-kappa B/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Recuento de Células , Neoplasias Colorrectales/patología , Neoplasias Esofágicas/patología , Femenino , Técnica del Anticuerpo Fluorescente Directa , Humanos , Masculino , Persona de Mediana Edad , Transducción de Señal , Neoplasias Gástricas/patología , Análisis de Matrices TisularesRESUMEN
Nuclear factor erythroid-related factor 2 (NRF2) encodes a transcription factor that induces expression of cytoprotective proteins upon oxidative stress and oncogenic NRF2 mutations have been found in lung and head/neck cancers that inactivate KEAP1-mediated degradation of NRF2. The aim of this study was to catalogue NRF2 mutations in other human cancers. For this, we analysed 1145 cancer tissues from carcinomas from oesophagus, skin, uterine cervix, lung, larynx, breast, colon, stomach, liver, prostate, urinary bladder, ovary, uterine cervix, and kidney, and meningiomas, multiple myelomas, and acute leukaemias by single-strand conformation polymorphism (SSCP) assay. We detected NRF2 mutations in oesophagus (8/70; 11.4%), skin (1/17; 6.3%), lung (10/125; 8.0%), and larynx (3/23; 13.0%) cancers. Of note, all of the 22 mutations except one were found in squamous cell carcinomas (SCCs) (95.5%). The mutations were observed within or near DLG and ETGE motifs that are important in NRF2 and KEAP1 interaction. All of the oesophageal SCCs and skin SCCs with the NRF2 mutations showed increased NRF2 expression in the nuclei. However, none of the SCCs from oesophagus and skin harboured KEAP1 mutation. Our study demonstrated here that NRF2 mutation occurs not only in lung and head/neck cancers, but also in oesophageal and skin cancers. Our data suggest that the NRF2 mutation plays a role in the development of SCC and is a feature of SCC.
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Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Mutación , Factor 2 Relacionado con NF-E2/genética , Neoplasias Cutáneas/genética , Carcinoma de Células Escamosas/metabolismo , Análisis Mutacional de ADN/métodos , ADN de Neoplasias/genética , Neoplasias Esofágicas/metabolismo , Femenino , Humanos , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo Conformacional Retorcido-Simple , Neoplasias Cutáneas/metabolismoRESUMEN
AIMS: Nuclear factor-kappa B (NF-kappaB) activation has been recognised as an important mechanism in the development of cancers. However, expression status of NF-kappaB-related proteins in oesophageal squamous cell carcinoma (ESCC) tissues is largely unknown. In this study, we analysed expressions of NF-kappaB members (p50/105, p52/p100 and RelA) and IKKepsilon in ESCC tissues. METHODS: We analysed the expression of p50/105, p52/p100, RelA and IKKepsilon in 58 ESCC patients' tissues by immunohistochemistry using a tissue microarray (TMA) method. RESULTS: Normal oesophageal squamous cells expressed p50/105, p52/p100 and RelA in 5%, 79% and 10% of the tissues in cytoplasm, respectively; however, only p52/p100 was expressed in the nuclei (12%). The cancer tissues expressed p50/105, p52/p100 and RelA in 93%, 95% and 95% in cytoplasm and/or nuclei, respectively. Nuclear immunostainings of NF-kappaB members p50/105, p52/p100 and RelA, which are considered activation of NF-kappaB signalling, were observed in 34%, 60% and 26% of the cancers, respectively. IKKepsilon is expressed in cytoplasm in 50% of the normal squamous tissues and 84% of the cancer tissues. However, none of the expression of p50/105, p52/p100, RelA or IKKepsilon was associated with pathological characteristics, including differentiation, depth of invasion and TNM stage. CONCLUSION: The increased nuclear expressions of p50/105, p52/p100 and RelA as well as increased cytoplasmic expression of IKKepsilon in the ESCC tissues compared to the normal squamous cells suggested that over-expression of these proteins may be related to activation of the NF-kappaB pathway and might play a role in the development of ESCC.
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Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Quinasa I-kappa B/metabolismo , Subunidad p50 de NF-kappa B/metabolismo , Subunidad p52 de NF-kappa B/metabolismo , Factor de Transcripción ReIA/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/patología , Núcleo Celular/metabolismo , Núcleo Celular/patología , Citoplasma/metabolismo , Citoplasma/patología , Neoplasias Esofágicas/patología , Esófago/metabolismo , Esófago/patología , Técnica del Anticuerpo Fluorescente Directa , Humanos , Técnicas para Inmunoenzimas , Persona de Mediana Edad , Invasividad Neoplásica , Proteínas de Neoplasias/metabolismo , Transducción de Señal , Análisis de Matrices TisularesRESUMEN
Activation of nuclear factor-kappa B (NF-kappaB) signaling is considered an important mechanism in the development of prostate cancers. A recent study revealed that IkappaB kinase epsilon (IKKepsilon), an activator of NF-kappaB, was overexpressed in breast cancers and acted as an oncogene. Expression of NF-kappaB members has been reported in prostate cancer tissues, but expression of IKKepsilon has not yet been studied in prostate cancers. In this study, we attempted to explore as to whether expressions of IKKepsilon and NF-kappaB members p50/105, p52/p100 and RelA are altered in prostate cancers. We analyzed the expression of IKKepsilon, p50/105, p52/p100 and RelA in 107 prostate adenocarcinoma tissues by immunohistochemistry using a tissue microarray (TMA) method. In the TMA, IKKepsilon is expressed in basal cells, but not in alveolar cells in normal prostate glands. IKKepsilon is expressed in 60.0% of prostate intraepithelial neoplasm (PIN) and 70.1% of the prostate cancers in the cytoplasm. Nuclear immunostainings of NF-kappaB members p50/105, p52/p100 and RelA, which are considered activation of NF-kappaB signaling, were observed respectively in 28.0%, 18.7% and 37.4% of the cancers. Nuclear staining was detected neither in normal alveolar cells nor in PIN. However, none of the expression of p50/105 nor p52/p100 nor RelA nor IKKepsilon was associated with pathologic characteristics, including size of the cancers, age, Gleason score and stage. The increased cytoplasmic expression of IKKepsilon as well as the increased nuclear expressions of p50/105, p52/p100 and RelA in the prostate cancers compared to normal alveolar cells suggested that overexpression of these proteins may be related to activation of the NF-kappaB pathway and might play a role in tumorigenesis of prostate cancers.
Asunto(s)
Adenocarcinoma/patología , Quinasa I-kappa B/biosíntesis , Subunidad p50 de NF-kappa B/biosíntesis , Subunidad p52 de NF-kappa B/biosíntesis , Neoplasias de la Próstata/patología , Factor de Transcripción ReIA/biosíntesis , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adulto , Anciano , Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Quinasa I-kappa B/análisis , Masculino , Persona de Mediana Edad , Subunidad p50 de NF-kappa B/análisis , Subunidad p52 de NF-kappa B/análisis , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Transducción de Señal , Análisis de Matrices Tisulares , Factor de Transcripción ReIA/análisisRESUMEN
Missense somatic mutations in IDH1 gene affecting codon 132 have recently been reported in glioblastoma multiforme (GBM) and other gliomas. The recurrent nature of the IDH1 mutations in the same amino acid strongly suggests that the mutations may play important roles in the pathogenesis of glial tumors. The aim of this study was to see whether the IDH1 codon 132 mutations occur in other human cancers besides glial tumors. We also attempted to confirm the occurrence of the IDH1 mutations in GBM of Korean patients. We have analyzed 1,186 cancer tissues from various origins, including carcinomas from breast, colon, lung, stomach, esophagus, liver, prostate, urinary bladder, ovary, uterine cervix, skin and kidney, and malignant mesotheliomas, primary GBM, malignant meningiomas, multiple myelomas and acute leukemias by single-strand conformation polymorphism analysis. We found four IDH1 codon 132 mutations in the GBM (4/25; 16.0%), two in the prostate carcinomas (2/75; 2.7%) and one in the B-acute lymphoblastic leukemias (B-ALL) (1/60; 1.7%), but none in other cancers. The IDH1 mutations consisted of five p.R132H and two p.R132C mutations. The data indicate that IDH1 codon 132 mutations occur not only in GBM, but also in prostate cancers and B-ALL. This study suggests that despite the infrequent incidence of the IDH1 mutations in prostate cancers and B-ALL, mutated IDH1 could be therapeutically targeted in these cancers and in glial tumors with the IDH1 mutations.
Asunto(s)
Neoplasias Encefálicas/genética , Codón , Glioblastoma/genética , Isocitrato Deshidrogenasa/genética , Mutación Missense , Secuencia de Bases , Cartilla de ADN , HumanosRESUMEN
Mounting evidence indicates that alterations of autophagy processes are directly involved in the development of many human diseases, including cancers. Autophagy-related gene (ATG) products are main players in the autophagy process. In humans there are 16 known ATG genes, of which four (ATG2B, ATG5, ATG9B and ATG12) have mononucleotide repeats with seven or more nucleotides. Frameshift mutations of genes with mononucleotide repeats are features of cancers with microsatellite instability (MSI). It is not known whether ATG genes with mononucleotide repeats are altered by frameshift mutations in gastric and colorectal carcinomas with MSI. For this, we analysed the mononecleotide repeats in ATG2B, ATG5, ATG9B and ATG12 in 32 gastric carcinomas with high MSI (MSI-H), 13 gastric carcinomas with low MSI (MSI-L), 43 colorectal carcinomas with MSI-H and 15 colorectal carcinomas with MSI-L by a single-strand conformation polymorphism (SSCP) analysis. We found ATG2B, ATG5, ATG9B and ATG12 mutations in 10, 2, 13 and 0 cancers, respectively. The mutations were detected in MSI-H cancers but not in MSI-L cancers. Gastric and colorectal cancers with MSI-H harboured one or more ATG mutations in 28.1% and 27.9%, respectively. Our data indicate that frameshift mutations in ATG genes with mononucleotide repeats are common in gastric and colorectal carcinomas with MSI-H, and suggest that these mutations may contribute to cancer development by deregulating the autophagy process.
Asunto(s)
Adenocarcinoma/genética , Autofagia/genética , Neoplasias Colorrectales/genética , Mutación del Sistema de Lectura , Neoplasias Gástricas/genética , Adenocarcinoma/patología , Proteína 12 Relacionada con la Autofagia , Proteína 5 Relacionada con la Autofagia , Proteínas Relacionadas con la Autofagia , Secuencia de Bases , Neoplasias Colorrectales/patología , ADN de Neoplasias/genética , Humanos , Proteínas de la Membrana/genética , Inestabilidad de Microsatélites , Proteínas Asociadas a Microtúbulos/genética , Estadificación de Neoplasias , Polimorfismo Conformacional Retorcido-Simple , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/genética , Neoplasias Gástricas/patologíaRESUMEN
Telomere maintenance is essential for continued cell proliferation and chromosome stability. Telomeres are maintained by telomerase and a collection of associated proteins. The telomeric protein telomeric repeat binding factor 1 (TRF1) negatively regulates telomere length by inhibiting access of telomerase at telomere termini. Here we report that TRF1 interacts with the beta subunit of casein kinase 2 (CK2) and serves as a substrate for CK2. CK2-mediated phosphorylation is required for the efficient telomere binding of TRF1 in vitro and in vivo. Inhibition of CK2 by the CK2 inhibitor 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole decreased the ability of TRF1 to bind telomeric DNA. The resulting telomere-unbound form of TRF1 was then ubiquitinated and degraded by the proteasome. Partial knockdown of CK2 by small interfering RNA resulted in removal of TRF1 from telomeres and subsequent degradation of TRF1. Mapping of the CK2 target site identified threonine 122 as a substrate in TRF1. A threonine to alanine change at this position led to a diminished DNA binding due to reduced dimerization of TRF1. In addition, phosphorylation of threonine 122 seemed critical for TRF1-mediated telomere length control. Our findings suggest that CK2-mediated phosphorylation of TRF1 plays an important role in modulating telomere length homeostasis by determining the levels of TRF1 at telomeres.