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Beta-tropomyosin (ß-tropomyosin, TPM2) has been found to be downregulated in colorectal cancer (CRC) in previous studies. In this study, we aimed to investigate the mechanisms and potential biological consequences of the downregulation of TPM2 in colorectal cancer. TPM2 expression in colorectal cancer was assessed by qRT-PCR and immunostaining. The biological functions of TPM2 were assessed in cell lines either overexpressing or underexpressingTPM2. Aberrant DNA methylation in the promoter region is associated with suppression of TPM2 expression in primary colorectal cancer tissue samples. Treatment with the demethylation agent 5-AZA can induceTPM2 expression in colorectal cancer cell lines. Reconstitution of TPM2 suppresses cell proliferation and migration in colorectal cancer cell lines, whereas the loss of TPM2 expression is associated with increased tumor proliferation and migration in vitro, which was accompanied by RhoA activation. In summary, our findings indicate that TPM2 appears to be commonly silenced by aberrant DNA methylation in colon cancer. TPM2 loss is associated with RhoA activation and tumor proliferation.
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Neoplasias Colorrectales/etiología , Metilación de ADN , Tropomiosina/genética , Proteína de Unión al GTP rhoA/fisiología , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Activación Enzimática , Humanos , Regiones Promotoras Genéticas , Transducción de SeñalRESUMEN
Phosphorylated p38 (p-p38) played a pivotal role in the regulation of disease progression and correlated with tumor prognosis. Here, we characterized the prognostic effect of p-p38 in colorectal cancer (CRC). Three hundred and sixteen CRC patients in stages I-III were recruited in this study. P-p38 expression was semi-quantitatively evaluated using tissue microarrays and immunohistochemistry staining. Overall survival (OS), disease-free survival (DFS), local failure-free survival (LFFS), and distant metastasis-free survival (DMFS) of patient subgroups, segregated by p-p38 expression level and clinical stage, were compared using Kaplan-Meier analysis. We found that p-p38 was overexpressed in 48.1 % (152/316) CRC tissues, whereas low or deficiently expressed in normal adjacent epithelia. Overexpression of p-p38 predicted poor OS (P < 0.001), DFS (P = 0.002), LFFS (P = 0.016), and DMFS (P = 0.025) in CRC. Importantly, patient subgroups in the early stage (stages I + II) and with low p-p38 had similar OS, PFS, LFFS, and DMFS probabilities to that of stage I, whereas those with high p-p38 were similar to stage III disease. In addition, for stage III disease, the subgroup with low p-p38 had a similar survival probability to that of stage I, whereas the subgroup with high p-p38 had the worst survival. Multivariate Cox analysis confirmed that p-p38 was indeed a significantly independent factor for death, recurrence, and distant metastases in CRC. Our results demonstrated that p-p38 was a negative independent prognostic factor for CRC. Complementing TNM staging with p-p38 might refine the risk definition more accurately for a subset of patients.
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Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/patología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Fosforilación , Pronóstico , Modelos de Riesgos Proporcionales , Curva ROC , Análisis de Matrices Tisulares , Adulto Joven , Proteínas Quinasas p38 Activadas por Mitógenos/análisisRESUMEN
BACKGROUND AND AIMS: Radiation enteritis (RE) has emerged as a significant complication that can progress to severe gastrointestinal disease and the mechanisms underlying its genesis remain poorly understood. The aim of this study was to identify temporal changes in protein expression potentially associated with acute inflammation and to elucidate the mechanism underlying radiation enteritis genesis. METHODS: Male Sprague-Dawley rats were irradiated in the abdomen with a single dose of 10 Gy to establish an in vivo model of acute radiation enteritis. Two-dimensional fluorescence difference gel electrophoresis, matrix-assisted laser desorption/ionization time-of-flight spectrometer (MALDI-TOF) tandem mass spectrometry, and peptide mass fingerprinting were used to determine differentially expressed proteins between normal and inflamed intestinal mucosa. Additionally, differentially expressed proteins were evaluated by KO Based Annotation System to find the biological functions associated with acute radiation enteritis. RESULTS: Intensity changes of 86 spots were detected with statistical significance (ratio ≥ 1.5 or ≤ 1.5, P < 0.05). Sixty one of the 86 spots were identified by MALDI-TOF/TOF tandem mass spectrometry. These radiation-induced proteins with biological functions showed that the FAS pathway and glycolysis signaling pathways were significantly altered using the KOBAS tool. CONCLUSIONS: Our results reveal an underlying mechanism of radiation-induced acute enteritis, which may help clarify the pathogenesis of RE and point to potential targets for therapeutic interventions.
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Enteritis/etiología , Redes y Vías Metabólicas/efectos de la radiación , Proteómica , Traumatismos Experimentales por Radiación , Transducción de Señal/fisiología , Animales , Modelos Animales de Enfermedad , Enteritis/metabolismo , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
C-Jun plays important roles in the development of multiple cancers, but no well-designed association studies have been conducted to assess the roles of its genetic polymorphisms in cancer risk. In a cohort of 1016 pairs of colorectal cancer (CRC) patients and matched cancer-free controls, we investigated two genetic polymorphisms in the promoter regions of the c-Jun (rs4646999, -673C > T and rs2760501, -1318T > G) via the Taqman assay and evaluated the association between two polymorphisms and risk of CRC. We found that both the -1318G and -673C variant genotypes were associated with an increased risk of CRC [-1318TG: odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.04-1.54; -1318GG: OR = 1.63, 95% CI = 1.03-2.60; -673CT: OR = 1.60, 95% CI = 1.23-2.07; -673CC: OR = 1.80, 95% CI = 1.36-2.37]. Haplotype association analysis showed that compared with the carriers of -1318T-673T haplotype, carriers of the -1318T-673C, -1318G-673T, and -1318G-673C haplotypes all had a significantly increased risk of CRC (P < 0.05 for all). The combined genotypes incorporating both polymorphisms obtained a more significantly additive risk of CRC (one variant genotype: OR = 1.81, 95% CI = 1.30-2.51; two variant genotype: OR = 2.42, 95% CI = 1.70-3.44). Moreover, we found that the change of the -1318T to G allele interact with the -673T to C allele elevated the transcription activity of the c-Jun, and we confirmed the same trends by analyzing c-Jun protein expression in the CRC tissues from patients carrying different number of variant genotypes. This study suggests that -673C > T and -1318T > G genetic variants in c-Jun promoter regions contribute to an increased risk of CRC, possibly by elevating the transcription activity and protein expression levels that appeared to upregulate activity of c-Jun thus tumorigenesis.
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Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Mutación , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-jun/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Plásmidos , Polimorfismo de Nucleótido SimpleRESUMEN
Mitogen-activated protein kinase kinase 4 (MKK4) is a critical mediator of stress-activated protein kinase signals that regulate apoptosis, inflammations and tumorigenesis. Several polymorphisms have been identified in the MKK4 gene. We hypothesized that genetic variants in the MKK4 promoter may alter its expression and thus cancer risk. In a case-control study of 1056 lung cancer cases and 1056 sex and age frequency-matched cancer-free controls, we genotyped two common polymorphisms in the MKK4 promoter region (-1304T>G and -1044A>T) with the Taqman assay, and we found that compared with the most common -1304TT genotype, carriers of -1304G variant genotypes had a decreased risk of lung cancer [odds ratio (OR) = 0.74; 95% confidence interval (CI) = 0.61-0.90 for TG, and OR = 0.62; 95% CI = 0.41-0.94 for GG] in an allele dose-response manner (adjusted P(trend) = 0.0005). Further stratification analysis showed that the protective role of the -1304G variant allele was more evident in low or normal body mass index (BMI) but restrained in the overweighters and that the -1304G variant genotypes interacted with BMI in reducing cancer risk (adjusted P(interaction) = 0.003). Moreover, the luciferase assay showed that the G allele in the promoter significantly increased the transcription activity of the MKK4 gene in vitro and that the MKK4 protein expression levels of the G variant carriers was significantly higher in tumor tissues than those of the -1304TT genotype. However, no significant association was observed between the -1044A>T polymorphism and risk of lung cancer. Our data suggest that the functional -1304G variant in the MKK4 promoter contributes to a decreased risk of lung cancer by increasing the promoter activity and that the G variant may be a marker for susceptibility to lung cancer.
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Variación Genética , Neoplasias Pulmonares/genética , MAP Quinasa Quinasa 4/genética , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Anciano , Portador Sano , Línea Celular Tumoral , Femenino , Genes Reporteros , Genotipo , Humanos , Desequilibrio de Ligamiento , Luciferasas/genética , Neoplasias Pulmonares/epidemiología , Masculino , Persona de Mediana Edad , Plásmidos , Polimorfismo Genético , Valores de Referencia , Factores de Riesgo , TransfecciónRESUMEN
Following publication of the original article [1], the authors reported an error that occurred during the production process.
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STUDY RATIONALE: The coexistence of KRAS and PIK3CA mutations in cells implies potential synergistic hyperactivation of the Ras/MAPK and PI3K/Akt oncogenic pathways. Therefore, it is desirable to investigate the concomitant mutations of KRAS and PIK3CA in colorectal cancer (CRC) samples and whether the concomitant mutations are associated with a poor prognosis in CRC patients. AIM: To investigate the clinicpathological characteristics and prognostic value of concomitant mutations of KRAS and PIK3CA in CRC samples. METHODS: In this study, a total of 655 CRC patients from the Sixth Affiliated Hospital of Sun Yat-sen University were enrolled from January to December 2015. Sanger sequencing was applied to survey the mutational status of hotspot regions in the open reading frames (ORFs) of the KRAS and PIK3CA genes. Clinicpathological parameters were collected and analyzed. The Kaplan-Meier method and Cox regression model were applied to determine the correlation between the KRAS and PIK3CA mutation statuses and survival. RESULTS: We found that KRAS and PIK3CA bi-mutations were significantly associated with aggressive clinicpathological features. Among the studied CRC patients, those with either KRAS mutations (Pâ¯=â¯0.004) or KRAS and PIK3CA bi-mutations (Pâ¯=â¯0.033) had poor overall survival (OS). In the multivariable analysis, KRAS mutations in exons 3 and 4 but not exon 2 with concomitant PIK3CA mutations were associated with a high risk of death (univariate HRâ¯=â¯8.05; 95% CI, 1.926-33.64, Pâ¯=â¯0.004; multivariate HRâ¯=â¯10.505; 95% CI, 2.304-47.905, Pâ¯=â¯0.002). CONCLUSION: The concomitant mutation statuses of KRAS and PIK3CA should be considered when the prognostic value of gene mutations is consulted in CRC patients.
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BACKGROUND: Interferon-alpha (IFNα) is a first-line treatment option for chronic hepatitis B virus (HBV) infection, but the severe systemic side-effects limited its clinical application. Interferon-lambda (IFNλ) with comparable antiviral activity and less toxic side-effects is thought to be a good alternative interferon to IFNα. Additionally, the gene vector mediated sustainably expression of therapeutic product in the target cells/tissue may overcome the shortcomings resulted from the short half-life of IFNs. RESULTS: We constructed a liver-specific IFNλ3-expressing minicircle (MC) vector under the control of a hepatocyte-specific ApoE promoter (MC.IFNλ3) and investigated its anti-HBV activity in a HBV-expressing hepatocyte-derived cell model (HepG2.2.15). As expected, the MC.IFNλ3 vector capable of expressing IFNλ3 in the recipient hepatocytes has demonstrated robust anti-HBV activity, in terms of suppressing viral antigen expression and viral DNA replication, via activation the interferon-stimulated gene (ISG) expression in HepG2.2.15 cells. CONCLUSIONS: Given the MC vector can be easily delivered into liver, the liver-targeted IFN gene-transfer (MC.IFNλ3), instead of systemic administrating IFN repeatedly, provides a promising concept for the treatment of chronic HBV infection.
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Antivirales , Virus de la Hepatitis B/fisiología , Hepatocitos/virología , Interferones/genética , Replicación Viral , Antivirales/metabolismo , Vectores Genéticos , Células Hep G2 , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/metabolismo , Hepatocitos/patología , Humanos , Interferones/metabolismo , Hígado/virologíaRESUMEN
INTRODUCTION: Although neoadjuvant chemo-radiotherapy (CRT) achieves low local recurrence rates in locally advanced rectal cancer (LARC), it raises a lot of concerns about long-term anal and sexual functions. We explored the efficacy of preoperative chemotherapy with mFOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) in patients with LARC. PATIENTS AND METHODS: Patients with LARC evaluated by pelvic magnetic resonance imaging (MRI) were enrolled in this trial. All received 4 to 6 cycles of mFOLFOXIRI. MRI was performed to assess clinical response after chemotherapy. Patients with mesorectal fascia-positive or ycT4a/b after re-evaluation would receive radiation before surgery, whereas responders would have immediate total mesorectal excision (TME). Adjuvant chemotherapy with mFOLFOX6 (folinic acid, 5-fluorouracil, and oxaliplatin) was recommended. The primary endpoint was the proportion of tumor downstaging to ypT0-2N0M0. The secondary endpoints were pathologic complete response rate (pCR), 3-year disease-free survival rate, and safety. RESULTS: Overall, 106 patients were enrolled and received neoadjuvant mFOLFOXIRI chemotherapy. A total of 103 participants underwent TME surgery. Among 103 patients who completed at least 4 cycles of preoperative chemotherapy, 2 received short-term radiation before TME, and 12 underwent long-term CRT after MRI evaluation. The pCR rate was 20.4%, and the tumor downstaging rate was 42.7%. Among patients without preoperative long-term radiotherapy, the pCR rate and tumor downstaging rate were 17.4% and 41.3%, respectively. Among the per-protocol population, the tumor downstaging rate was 48.1%, and the pCR rate was 20.3%. The chemotherapy-related toxicity was well-tolerated. CONCLUSION: Neoadjuvant chemotherapy with mFOLFOXIRI and selective radiation does not seem to compromise outcomes in LARC. It could be a reasonable alternative to CRT in previously untreated patients with LARC.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante/mortalidad , Terapia Neoadyuvante/mortalidad , Neoplasias del Recto/tratamiento farmacológico , Adenocarcinoma/patología , Adolescente , Adulto , Anciano , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Irinotecán/administración & dosificación , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Oxaliplatino/administración & dosificación , Cuidados Preoperatorios , Pronóstico , Estudios Prospectivos , Neoplasias del Recto/patología , Tasa de Supervivencia , Adulto JovenRESUMEN
Long noncoding RNAs (lncRNAs) have been emerging as master regulators of tumor growth and metastasis, but the functions and underlying mechanisms of lncRNAs in colorectal cancer (CRC) still need to be clarified. Here, we found a novel lncRNA u50535, which was greatly overexpressed in CRC tissues and was associated with poor prognosis in CRC patients. Function studies showed that u50535 was an oncogene in CRC both in vitro and in vivo. In mechanism, through RNA sequencing and rescue assay, we found that u50535 activates CCL20 signaling to promote cell proliferation and migration in CRC. Taken together, these findings suggest that u50535 can promote CRC growth and metastasis and may serve as a potential biomarker in CRC.
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Quimiocina CCL20/metabolismo , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , ARN Largo no Codificante/metabolismo , Animales , Apoptosis/genética , Apoptosis/fisiología , Ciclo Celular/genética , Ciclo Celular/fisiología , Movimiento Celular/genética , Movimiento Celular/fisiología , Proliferación Celular/genética , Proliferación Celular/fisiología , Neoplasias Colorrectales/genética , Transición Epitelial-Mesenquimal/genética , Transición Epitelial-Mesenquimal/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Células HCT116 , Humanos , Hibridación Fluorescente in Situ , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , ARN Largo no Codificante/genética , Transducción de Señal/genética , Transducción de Señal/fisiologíaAsunto(s)
Neoplasias de la Médula Ósea , Neoplasias Óseas , Coagulación Intravascular Diseminada , Neoplasias Gástricas , Neoplasias de la Médula Ósea/secundario , Neoplasias Óseas/secundario , Coagulación Intravascular Diseminada/complicaciones , Coagulación Intravascular Diseminada/patología , Humanos , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/patologíaRESUMEN
Spleen tyrosine kinase (SYK) has been reported as a potential tumor suppressor in colorectal cancer (CRC). However, the role of alternative splicing of SYK in carcinogenesis remains unclear. In the present study, SYK isoforms were overexpressed in the human CRC HCT 116 cell line using lentiviral expression vectors to investigate the biological functions of full length SYK [SYK(L)] and short form SYK [SYK(S)] in CRC. Real-time cellular analysis and the 5-ethynyl-2-deoxyuridine assay were used to detect the effects of SYK(L) and SYK(S) on cell proliferation. Cell cycle progression and migration were assessed via flow cytometry and Transwell assays, respectively. The results revealed that the recombinant lentivirus with SYK(L) overexpression significantly suppressed the proliferation and metastasis of CRC cells, while SYK(S) overexpression did not. In addition, MTS assays demonstrated that SYK(L) and SYK(S) increased the cellular sensitivity to 5-fluorouracil (5-FU), suggesting that SYK(L) and 5-FU produce a significant synergistic effect on CRC cell proliferation, while SYK(S) has an effect on modulating CRC 5-FU sensitivity. Furthermore, quantitative polymerase chain reaction results revealed that SYK(L) was downregulated in 69% of 26 pairs of CRC and adjacent non-cancerous tissues, whereas SYK(S) exhibited no significant differences between tumor and normal tissues. Overall, the present data provides evidence that SYK(L) is a tumor suppressor in CRC, and both SYK(L) and SYK(S) may serve as important predictors in the chemotherapeutic treatment of CRC.
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Accumulating evidence reveals that long non-coding RNA (lncRNA) is essential for tumorigenesis and progression, but little is known about its roles and mechanisms in metastatic colorectal cancer (CRC). This study aimed to detect expression level and prognostic role of lncRNACTD903 in CRC patients, which was selected based on one microarray data. The effects on cell invasion, migration and proliferation were investigated after silencing or overexpression of CTD903 in CRC cell lines. We also observed the EMT (epithelial-mesenchymal transition) phenomenon and effect on cell adhesion. The associations between CTD903 and EMT markers, such as E-cadherin, N-cadherin, ß-catenin, ZEB1, ZO-1, Snail, and Twist, were determined by western blotting. Our results showed lncRNA-CTD903 expression was strongly upregulated in 115 CRC patients, comparing to adjacent normal tissues. CTD903 was proven to be an independent predicted factor of favorable prognosis in CRC patients by using multivariate Cox proportional hazards model. After knockdown of CTD903 in RKO and SW480, both cell invasion and migration increased, and cells exhibited EMT-like appearance, along with reduced adhering ability. Moreover, overexpression of CTD903 in DLD1 and HCT116 reversed these phenotypes. Furthermore, downregulation of CTD903 enhanced Wnt/ß-catenin activation and subsequently increased transcription factors (Twist and Snail) expression, along with increased mesenchymal marker Vimentin and decreased epithelial marker ZO-1 level, while overexpressed CTD903 confirmed these associations. In conclusion, this study shows that LncRNA-CTD903 acts as a tumor suppressor in CRC and can inhibit cell invasion and migration through repressing Wnt/ß-catenin signaling, which plays important roles in EMT and CRC metastasis.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Regulación hacia Abajo , ARN Largo no Codificante/genética , Células CACO-2 , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Transición Epitelial-Mesenquimal , Femenino , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Células HT29 , Humanos , Masculino , Invasividad Neoplásica , Pronóstico , Vía de Señalización WntRESUMEN
PURPOSE: The KRAS gene frequently mutates in colorectal cancer (CRC). Here we investigated the prognostic and predictive role of KRAS mutation in patients with stage II or III CRC. EXPERIMENTAL DESIGN: A consecutive cohort of patients with stage II or III CRC from a single center database was studied. The association between KRAS status, adjuvant FOLFOX therapy, and 3-year disease-free survival (3-y DFS) was analyzed. RESULTS: Of our 433 patients, 166 (38.3%) exhibited the KRAS mutation. Among the 190 patients who did not receive adjuvant therapy, those with KRAS mutation tumors had a worse 3-y DFS (hazard ratio [HR], 1.924; 95% confidence interval [CI], 1.078-3.435; P = 0.027). Among patients who received adjuvant chemotherapy, KRAS mutation was not correlated with worse 3-y DFS (HR, 1.083; 95% CI, 0.618-1.899; P = 0.781). Adjuvant chemotherapy improved 3-y DFS only among patients with KRAS mutant tumors (78.0% vs 69.2%) on multivariate analysis adjusted for age, stage, grade, site, vessel invasion, and carcinoembryonic antigen level (HR, 0.454; 95% CI, 0.229-0.901; P = 0.024). In contrast, there was no benefit of adjuvant chemotherapy in the KRAS wild-type group (84.3% vs 82.0%). CONCLUSIONS: KRAS mutation indicates poor prognosis. FOLFOX adjuvant chemotherapy benefits patients with stage II or III colorectal cancer with KRAS mutant tumors and is worth further investigation.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Genes ras , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Pronóstico , Adulto JovenRESUMEN
Long non-coding RNA, urothelial cancer associated 1 (UCA1), is reported to play a critical role in progression of carcinogenesis. In the present study, we identified differential expression of UCA1 in colorectal cancer (CRC) and paired peritumoral tissues using gene expression microarray analyses. qPCR analysis confirmed that UCA1 was upregulated in CRC (p<0.001) and the expression of UCA1 was statistically correlated with lymph node metastasis (P=0.040), distant metastasis (P=0.043) and tumor stage (P=0.010). Kaplan-Meier analysis indicated that patients with high UCA1 expression had a poor prognosis. Moreover, multivariate analysis identified UCA1 overexpression as an independent predictor for CRC. We also found that knockdown of UCA1 significantly suppressed cell proliferation and metastasis in CRC cells. Flow cytometry assays showed UCA1 silencing induced G0/G1 growth arrest and apoptosis of CRC cells. To further investigate the regulatory mechanisms of UCA1, we identified that Ets-2 bound to the UCA1 core promoter using luciferase assays. Collectively, our findings suggested that UCA1 might be an important prognostic indicator in CRC and may be a potential target for diagnosis and gene therapy.
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Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/patología , ARN Largo no Codificante/biosíntesis , Apoptosis/genética , Proliferación Celular/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Femenino , Citometría de Flujo , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutagénesis Sitio-Dirigida , Invasividad Neoplásica/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , Pronóstico , Modelos de Riesgos Proporcionales , ARN Largo no Codificante/análisis , ARN Interferente Pequeño , TransfecciónRESUMEN
BACKGROUND: Late intestinal toxicity after radiotherapy (LITAR) not only limits the radiation dose, which subsequently leads to unfavorable clinical outcomes, but also significantly lowers the quality of life in an increasing number of cancer survivors. Therefore, identifying clinical risk factors for LITAR is important for establishing a predictive model in the clinical setting of decision-making for these patients. This review aims to systematically summarize and clarify the clinical factors that can be potentially associated with an increased risk of moderate/severe LITAR in patients with abdominal or pelvic malignancies. METHODS/DESIGN: MEDLINE, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, Scopus, Google Scholar and Chinese BioMed will be systematically searched to identify appropriate studies. Citations of the retrieved studies and recent reviews will also be searched separately by case.The enrolled studies should at least have the following information: (1) a clear definition and information on the LITAR severity; (2) assess clinical factors for moderate/severe toxicity with adjusted risk estimates; (3) have a cohort, case-control, randomized controlled trial and controlled clinical trial study design.Two authors will independently review the abstract and full text of retrieved studies, extract data from eligible studies and assess the risk of bias. Disagreements will be discussed among reviewers until a consensus is reached. The effect of identified risk factors will be displayed in forest plots. If the information is sufficient, results will be synthesized by a meta-analysis with the random effects model to pool the estimate of risk posed by clinical factors. Subgroup and sensitivity analysis will be used to explore the sources of heterogeneity. DISCUSSION: This review will summarize the evidence of clinical risk factors for moderate/severe LITAR. The results may help guide decision-making and minimize the side effects of therapeutic modalities in the clinical setting.
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Enteritis/etiología , Intestinos/efectos de la radiación , Metaanálisis como Asunto , Neoplasias/radioterapia , Traumatismos por Radiación/etiología , Radiación Ionizante , Proyectos de Investigación , Humanos , Neoplasias/complicaciones , Factores de Riesgo , Revisiones Sistemáticas como AsuntoRESUMEN
p38 plays a critical role in the proliferation, survival, migration and metastasis of colorectal cancer (CRC) cells. The present study assessed the correlation between a single nucleotide polymorphism (SNP) in the p38ß promoter region (rs2235356, -1628A>G) and the predisposition of individuals to sporadic CRC in a case-control study. A genotyping method was developed to detect this SNP, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. A logistic regression analysis was used to determine the odds ratio (OR) and 95% confidence interval (CI). It was revealed that the -1628G variant allele was correlated with an increased risk of CRC (OR, 1.99; 95% CI, 1.60-2.47; P<0.0001). An in silico analysis revealed several transcription factors that either acquired or lost the ability to bind to -1628AA in the p38ß promoter region due to the SNP. Therefore, this allelic variant may be a genetic modifier for CRC susceptibility.
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Snail and Twist, transcriptional repressors of E-cadherin as well as inducers of epithelial-mesenchymal transition, play pivotal roles in tumor invasion and metastasis. We investigated the expression of Snail, Twist, and E-cadherin by immunohistochemistry in 193 colorectal cancers, including 79 with positive lymph nodes, 36 with tumor deposits, 39 with both, and 39 with no metastases. Snail was expressed to a greater extent in the group with positive lymph nodes (68.4%), whereas Twist was overexpressed in patients with other metastases (75.0%). Ectopic expression of Snail and Twist correlated with reduced membranous expression of E-cadherin. Importantly, Snail overexpression correlated significantly with lymph node metastasis (P < .0001), whereas Twist up-regulation correlated strongly with other metastases (P < .0001). Multivariate logistic regression analysis showed that Snail was an independent predictor of lymph node metastasis (odds ratio, 4.445; 95% confidence interval, 2.250-8.781; P < .0001), whereas Twist displayed predictive value for metastasis formation (odds ratio, 5.606; 95% confidence interval, 2.829-11.111; P < .0001), suggesting that lymph node and other metastases may follow different signaling pathways. In conclusion, ectopic expression of Snail and Twist contributed to lymph node and disseminated metastasis, respectively, by reducing E-cadherin expression, providing a novel role for Snail and Twist in the progression of colorectal cancer.
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Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción/metabolismo , Proteína 1 Relacionada con Twist/metabolismo , Cadherinas/metabolismo , Neoplasias Colorrectales/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Ganglios Linfáticos/metabolismo , Metástasis Linfática , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Factores de Transcripción de la Familia Snail , Análisis de Matrices Tisulares , Regulación hacia ArribaRESUMEN
Mitogen/extracellular signal-regulated kinase kinase-5 (MEK5), which belongs to a network of mitogen-activated protein kinase pathways, play a pivotal role in carcinogenesis. The purpose of this study was to investigate whether variants in the MEK5 gene promoter were involved in susceptivity of individuals to sporadic colorectal cancer (CRC). In the present hospital-based case-control study of 737 patients with sporadic CRC and 703 healthy control subjects in a southern Chinese population, the two polymorphisms of MEK5 promoter (i.e., rs7172582C>T and rs3743354T>C) were genotyped by TaqMan assay. There were significant differences between cases and controls in the genotype and allele distribution of the MEK5 gene rs3743354T>C polymorphism. The rs3743354 CC genotype was associated with a significantly decreased risk of CRC when compared with the TT genotype (adjusted odds ratios [ORs]=0.43; 95% confidence interval [CI], 0.24-0.77). Compared to the T allele, a significant correlation was detected between the presence of the C allele and decreased risk of CRC (adjusted OR=0.79; 95% CI, 0.61-0.94). The decreased risk of CRC associated with rs3743354 variant genotypes (i.e., CT+CC) was found in the smoker subgroup (adjusted OR=0.63; 95% CI=0.45-0.88). Further, environmental factors, including smoking and drinking, interacted with rs3743354C variant genotypes to reduce CRC risk. Western blot analysis showed that the levels of MEK5 protein in sporadic CRC neoplastic tissues and adjacent normal colorectal epithelium tissues were lower in the carriers of rs3743354 CC genotypes than that in those with rs3743354 TT genotypes or those with rs3743354 TC genotypes. However, no significant association was found between the rs7172582C>T polymorphism and risk of CRC. These data indicate that the rs3743354 polymorphism in the MEK5 promoter may affect the risk of developing CRC.
Asunto(s)
Pueblo Asiatico/genética , Neoplasias Colorrectales/genética , MAP Quinasa Quinasa 5/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Anciano , Femenino , Genética de Población , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
OBJECTIVE: To evaluate the safety and efficacy of self-expending metallic stents (SEMS) as bridge to surgery versus emergency surgery for left-sided malignant colorectal obstruction. METHODS: A comprehensive literature search of CENTRAL, PubMed, EMBASE, Medline, Ovid LWW, CMB, CNKI and Wanfang Databases were performed for all randomized controlled trials or retrospective studies comparing self-expending metallic stents as bridge to surgery(SABS group) with emergency surgery (ES group). A meta-analysis was carried out by RevMan5.1 software on the outcomes concerning safety and efficacy of the two groups. RESULTS: Fourteen studies matched the criteria including 1083 patients. Five were randomized controlled trials and nine were retrospective analysis. Compared with the ES group, the SABS group had a lower short-term mortality(RR=0.52, 95% CI:0.30-0.93, P<0.05), lower overall complications(RR=0.46, 95% CI:0.31-0.70, P<0.05), higher resection rate(RR=1.90, 95%CI:1.33-2.70, P<0.01), shorter operative time(MD=-59.77, 95%CI:-87.51--32.04, P<0.01), and shorter interval to first flatus(MD=-10.78, 95%CI:-16.67--4.90, P<0.01). There were no statistically significant differences between the two groups in permanent stomy and hospital stay. CONCLUSION: The safety and efficacy of self-expending metallic stents as bridge to surgery for left-sided malignant colorectal obstruction is superior to emergency surgery.