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The inconsistency between mismatch repair (MMR) protein immunohistochemistry (IHC) and microsatellite instability PCR (MSI-PCR) methods has been widely reported. We aim to investigate the prognosis and the effect of immunotherapy in dMMR by IHC but MSS by MSI-PCR (dMMR&MSS) colorectal cancer (CRC) patients. A microsatellite instability (MSI) predicting model was established to help find dMMR&MSS patients. MMR and MSI states were detected by the IHC and MSI-PCR in 1622 CRC patients (ZS6Y-1 cohort). Logistic regression analysis was used to screen clinical features to construct an MSI-predicting nomogram. We propose a new nomogram-based assay to find patients with dMMR&MSS, in which the MSI-PCR assay only detects dMMR patients with MSS predictive results. We applied the new strategy to a random cohort of 248 CRC patients (ZS6Y-2 cohort). The consistency of MMR IHC and MSI-PCR in the ZS6Y-1 cohort was 95.7% (1553/1622). Both pMMR&MSS and dMMR&MSS groups experienced significantly shorter overall survival (OS) than those in dMMR by IHC and MSI-H by MSI-PCR (dMMR&MSI-H) group (hazard ratio [HR] = 2.429, 95% confidence interval [CI]: 1.89-3.116, p < .01; HR = 21.96, 95% CI: 7.24-66.61, p < .01). The dMMR&MSS group experienced shorter OS than the pMMR&MSS group, but the difference did not reach significance (log rank test, p = .0686). In the immunotherapy group, the progression-free survival of dMMR&MSS patients was significantly shorter than that of dMMR&MSI-H patients (HR = 13.83, 95% CI: 1.508-126.8, p < .05). The ZS6Y-MSI-Pre nomogram (C-index = 0.816, 95% CI: 0.792-0.841, already online) found 66% (2/3) dMMR&MSS patients in the ZS6Y-2 cohort. There are significant differences in OS and immunotherapy effect between dMMR&MSI-H and dMMR&MSS patients. Our prediction model provides an economical way to screen dMMR&MSS patients.
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Neoplasias Colorrectales , Reparación de la Incompatibilidad de ADN , Inmunoterapia , Inestabilidad de Microsatélites , Nomogramas , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/inmunología , Femenino , Masculino , Pronóstico , Persona de Mediana Edad , Reparación de la Incompatibilidad de ADN/genética , Inmunoterapia/métodos , Anciano , Inmunohistoquímica , Adulto , Biomarcadores de Tumor/genéticaRESUMEN
The twisted bilayer system provides an excellent platform for the study of flatbands. In this work, we propose a bilayer hexagonal boron nitride (h-BN)-like surface plasmon crystal at a large twist angle of 38.213° due to the interlayer strong coupling, in which the adjacent pillars are in different radii. We numerically and theoretically calculate the band structure while tuning the pillar radius ratio (PRR) and the interlayer separation distance. As a result, both increasing the PRR and decreasing the separation distance contribute to the transition from weak coupling to strong coupling, leading to the flatbands with slow velocity and large density of state. Consequently, the in-layer geometry as well as the separation distance offers the degree of freedom to achieve flatbands in the bilayer surface plasmon crystal. Our work provides a fundamental understanding of the band structure of the twisted bilayer photonic system, which enriches the methods to obtain flatbands at a large twist angle.
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The atmospheric dust has a great negative impact on the societal harmonious development that starves for an efficient dust suppressant. This paper proposes a novel AES/polyacrylamide strengthen foam (APSF) to improve the dust trapping effectiveness. The APSF structure property and dust suppression capacity are studied and evaluated through the molecular dynamics simulation and experimental tests. The results express that APSF exhibits the stronger structure stability, superior water retention, and slower drainage performance than the traditional water-based foam (WBF). APSF dynamic simulation is studied by the relative concentration, radial distribution function, head group orientation, and mean square displacement. Research shows that APSF introduces water to thicken the hydration layer. The interaction strength between water and surfactant head groups is enhanced by 22.62 and 31.37% in the first and second hydrated water shells. APSF improves the sodium fatty alcohol ether sulfate (AES) orientation and weakens the diffusion of water molecules, which favors the foam stability. APSF exerts a better wettability on the coal dust through the wet settlement and contact angle tests. The APSF liquid film thickness reduces to 58.05 from 64.80 µm that is 3.14 times of WBF according to the foam liquid film decay experiment. Fourier transform infrared (FTIR) spectroscopy analysis indicates that there is an evident reinforcement on the coal surface absorption peak intensity of hydroxyl- and oxygen-containing functional groups treated by APSF. FTIR results are further determined by energy-dispersion spectrum analysis.
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TGFß induces the differentiation of hepatic stellate cells (HSCs) into tumor-promoting myofibroblasts but underlying mechanisms remain incompletely understood. Because endocytosis of TGFß receptor II (TßRII), in response to TGFß stimulation, is a prerequisite for TGF signaling, we investigated the role of protein diaphanous homolog 1 (known as Diaph1 or mDia1) for the myofibroblastic activation of HSCs. Using shRNA to knockdown Diaph1 or SMIFH2 to target Diaph1 activity of HSCs, we found that the inactivation of Diaph1 blocked internalization and intracellular trafficking of TßRII and reduced SMAD3 phosphorylation induced by TGFß1. Mechanistic studies revealed that the N-terminal portion of Diaph1 interacted with both TßRII and Rab5a directly and that Rab5a activity of HSCs was increased by Diaph1 overexpression and decreased by Diaph1 knockdown. Additionally, expression of Rab5aQ79L (active Rab5a mutant) increased whereas the expression of Rab5aS34N (inactive mutant) reduced the endosomal localization of TßRII in HSCs compared to the expression of wild-type Rab5a. Functionally, TGFß stimulation promoted HSCs to express tumor-promoting factors, and α-smooth muscle actin, fibronection, and CTGF, markers of myofibroblastic activation of HSCs. Targeting Diaph1 or Rab5a suppressed HSC activation and limited tumor growth in a tumor implantation mouse model. Thus, Dipah1 and Rab5a represent targets for inhibiting HSC activation and the hepatic tumor microenvironment.
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Endocitosis/fisiología , Forminas/metabolismo , Células Estrelladas Hepáticas/metabolismo , Miofibroblastos/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Proteínas de Unión al GTP rab5/metabolismo , Actinas/metabolismo , Animales , Biomarcadores/metabolismo , Línea Celular , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Transdiferenciación Celular/fisiología , Células HT29 , Células Estrelladas Hepáticas/fisiología , Humanos , Masculino , Ratones , Ratones Desnudos , Miofibroblastos/fisiología , Fosforilación/fisiología , Transducción de Señal/fisiología , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
The incidence of colorectal cancer (CRC) is increasing in China. Here, we aimed to evaluate the latest demographic trends and KRAS/BRAF mutations status of Chinese CRC. Five thousand five hundred and forty-six CRC patients diagnosed from 2010 to 2017 were involved. KRAS exon 2 and BRAFV600E mutations were detected by Sanger sequencing and high-resolution melting analysis or allelic-specific probe method. Gene mutation profiles and clinicopathologic characteristics of 5495 patients were analyzed. The joinpoint regression model was used to predict the demographic data in 2018. We found KRAS exon 2 and BRAFV600E mutation rates were 37.7 and 2.8% in CRC patients. Tumors with KRAS exon 2 mutations were more likely to be present in female and patients aged older than 75 years, right colon and have well-differentiated histology. Tumors with BRAFV600E mutations were more likely to be present in the female, right colon and have poorly differentiated histology. From 2010 to 2017, the percentage of colon cancer and tubular adenocarcinoma in CRC increased substantially (from 39.3 to 51.8%, from 78.6 to 93.4%, respectively). The percentage of right colon cancer increased from 18.3 to 20.5%, which predictively may keep at 22.6% in 2018. The rise trends for patients with moderate differentiation tumor or KRAS exon 2 mutated tumor were apparent (from 50.3 to 78.6%, from 32.8 to 39.7%, respectively). In conclusion, in recent 8 years, there is a shift to the colon, especially right colon in the incidence of Chinese CRC. Moreover tubular adenocarcinoma is becoming the primary histology type.
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Adenocarcinoma/epidemiología , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Adenocarcinoma/genética , Adenocarcinoma/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , China/epidemiología , Neoplasias Colorrectales/patología , Demografía , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Mutación/genética , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
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
PURPOSE: To investigate the clinical impact of plan complexity on the local recurrence-free survival (LRFS) of non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT). METHODS: Data from 123 treatment plans for 113 NSCLC patients were analyzed. Plan-averaged beam modulation (PM), plan beam irregularity (PI), monitor unit/Gy (MU/Gy) and spherical disproportion (SD) were calculated. The γ passing rates (GPR) were measured using ArcCHECK 3D phantom with 2 %/2mm criteria. High complexity (HC) and low complexity (LC) groups were statistically stratified based on the aforementioned metrics, using cutoffs determined by their significance in correlation with survival time, as calculated using the R-3.6.1 packages. Kaplan-Meier analysis, Cox regression, and Random Survival Forest (RSF) models were employed for the analysis of local recurrence-free survival (LRFS). Propensity-score-matched pairs were generated to minimize bias in the analysis. RESULTS: The median follow-up time for all patients was 25.5 months (interquartile range 13.4-41.2). The prognostic capacity of PM was suggested using RSF, based on Variable Importance and Minimal Depth methods. The 1-, 2-, and 3-year LRFS rates in the HC group were significantly lower than those in the LC group (p = 0.023), when plan complexity was defined by PM. However, no significant difference was observed between the HC and LC groups when defined by other metrics (p > 0.05). All γ passing rates exceeded 90.5 %. CONCLUSIONS: This study revealed a significant association between higher PM and worse LRFS in NSCLC patients treated with SBRT. This finding offers additional clinical evidence supporting the potential optimization of pre-treatment quality assurance protocols.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Radiocirugia , Planificación de la Radioterapia Asistida por Computador , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Humanos , Neoplasias Pulmonares/radioterapia , Masculino , Femenino , Planificación de la Radioterapia Asistida por Computador/métodos , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Recurrencia Local de Neoplasia , Supervivencia sin Enfermedad , Estudios RetrospectivosRESUMEN
Background: MLH1 promoter methylation analysis is recommended in screening for Lynch syndrome (LS) in patients with MLH1-deficient colorectal cancer (CRC). The study aims to identify specific methylation regions in the MLH1 promoter and to evaluate the clinicopathologic characteristics of and prognosis for patients with MLH1 methylation. Methods: A total of 580 CRC cases were included. The DNA mismatch repair (MMR) protein expression was assessed by using immunohistochemistry (IHC). The methylation status of the Regions A, B, C, D, and E in the MLH1 promoter was tested by using bisulfite sequencing PCR. The specificities of the five regions were calculated. Associations between MLH1 methylation and clinicopathologic characteristics were evaluated. Kaplan-Meier analyses for overall survival (OS) were carried out. Results: In 580 CRC cases, the specificities of the methylation test in Regions D and E were both 97.8%. In the MLH1-deficient CRCs, the frequencies of MLH1 methylation and BRAFV600E mutation were 52.6% and 14.6%, respectively; BRAFV600E mutation occurred in 27.7% of patients with MLH1-methylated CRC. In the MMR-deficient patients, compared with MLH1 unmethylation, MLH1 methylation was more common in patients who were aged ≥50 years, female, had no family history of LS-related tumors, and had tumors located at the right colon. In the MMR-deficient patients, the MLH1-methylated cases had lower OS rates than the unmethylated cases with a family history of LS-related tumors (P = 0.047). Conclusions: Regions D and E in the MLH1 promoter are recommended for determining the MLH1 methylation status in screening for LS in MLH1-deficient CRC. In MMR-deficient patients, the MLH1-methylated cases had a worse OS than the unmethylated cases with a family history of LS-related cancer.
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Zinc finger protein 180 (ZNF180) is a multifunctional protein that interacts with nucleic acids and regulates various cellular processes; however, the function of ZNF180 in colorectal cancer (CRC) remains unclear. The present study investigated the role and function of ZNF180 in CRC, and aimed to reveal the underlying molecular mechanism. The results revealed that ZNF180 was downregulated in CRC tissues and was associated with a good prognosis in patients with CRC. Additionally, the expression of ZNF180 was downregulated by methylation in CRC. In vivo and in vitro experiments revealed that ZNF180 overexpression was functionally associated with the inhibition of cell proliferation and the induction of apoptosis. Mechanistically, chromatin immunoprecipitationPCR and luciferase assays demonstrated that ZNF180 markedly regulated the transcriptional activity of methyltransferase 14, N6adenosinemethyltransferase noncatalytic subunit (METTL14) by directly binding to and activating its promoter region. Simultaneous overexpression of ZNF180 and knockdown of METTL14 indicated that the reduction of METTL14 could suppress the effects of ZNF180 on the induction of apoptosis. Clinically, the present study observed a significant positive correlation between ZNF180 and METTL14 expression levels, and low expression of ZNF180 and METTL14 predicted a poor prognosis in CRC. Overall, these findings revealed a novel mechanism by which the ZNF180/METTL14 axis may modulate apoptosis and cell proliferation in CRC. This evidence suggests that this axis may serve as a prognostic biomarker and therapeutic target in patients with CRC.
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Apoptosis , Proliferación Celular , Neoplasias Colorrectales , Regulación Neoplásica de la Expresión Génica , Metiltransferasas , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Metiltransferasas/genética , Metiltransferasas/metabolismo , Apoptosis/genética , Proliferación Celular/genética , Masculino , Femenino , Pronóstico , Persona de Mediana Edad , Línea Celular Tumoral , Animales , Activación Transcripcional , Ratones , Regiones Promotoras Genéticas , Anciano , Regulación hacia Abajo , Metilación de ADNRESUMEN
Cholesterol metabolism has important roles in maintaining membrane integrity and countering the development of diseases such as obesity and cancers. Cancer cells sustain cholesterol biogenesis for their proliferation and microenvironment reprograming even when sterols are abundant. However, efficacy of targeting cholesterol metabolism for cancer treatment is always compromised. Here it is shown that CSN6 is elevated in HCC and is a positive regulator of hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) of mevalonate (MVA) pathway to promote tumorigenesis. Mechanistically, CSN6 antagonizes speckle-type POZ protein (SPOP) ubiquitin ligase to stabilize HMGCS1, which in turn activates YAP1 to promote tumor growth. In orthotopic liver cancer models, targeting CSN6 and HMGCS1 hinders tumor growth in both normal and high fat diet. Significantly, HMGCS1 depletion improves YAP inhibitor efficacy in patient derived xenograft models. The results identify a CSN6-HMGCS1-YAP1 axis mediating tumor outgrowth in HCC and propose a therapeutic strategy of targeting non-alcoholic fatty liver diseases- associated HCC.
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Carcinoma Hepatocelular , Hidroximetilglutaril-CoA Sintasa , Neoplasias Hepáticas , Proteínas Represoras , Proteínas Señalizadoras YAP , Humanos , Carcinoma Hepatocelular/metabolismo , Colesterol/metabolismo , Hidroximetilglutaril-CoA Sintasa/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Represoras/metabolismo , Microambiente Tumoral , Ubiquitina/metabolismo , Proteínas Señalizadoras YAP/metabolismoRESUMEN
CD133-positive cancer stem cells in colon cancer are resistant to conventional chemotherapy. The aim of the present study was to investigate the effect of celecoxib, a COX-2 inhibitor, on CD133 expression in HT29 and DLD1 cells. HT29 and DLD1 cells were treated with celecoxib using different concentrations and duration. CD133 expression was detected by flow cytometry, Western blotting, immunofluorescence, and quantitative real-time PCR. Wnt signaling pathway activity was measured by luciferase assay and gene expression changes were monitored using microarray analysis. HT29 cells showed significantly decreasing levels of CD133 expression with increasing concentrations of or duration of exposure to celecoxib. CD133 mRNA relative expression in HT29 and DLD1 cells also decreased with drug exposure. Furthermore, Wnt activation in HT29 and DLD1 cells decreased with celecoxib treatment. Gene expression microarray showed stemness genes, including Lgr5, Oct4, Prominin-1, Prominin-2, CXCR4, E2F8, CDK-2, were downregulated and differentiation genes, including CEACAM5, GDF, ADFP, ICAM1, were upregulated. Our results show that CD133 expression was downregulated by celecoxib through inhibition of the Wnt signaling pathway, which may be lead to cell differentiation.
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Antígenos CD/biosíntesis , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Glicoproteínas/biosíntesis , Pirazoles/farmacología , Sulfonamidas/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Antígeno AC133 , Antígenos CD/genética , Celecoxib , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glicoproteínas/genética , Células HT29 , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Péptidos/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genéticaRESUMEN
AIMS: Due to the lack of large clinical cohorts in the Chinese populations with colorectal cancer (CRC) and gastric cancer (GC), there is no consensus among the preferred panel for microsatellite instability (MSI)-PCR testing. This study aims to evaluate a more appropriate panel. METHODS: We tested the MSI status of 2572 patients with CRC and GC using the NCI panel and 2 mononucleotide panels (5 and 6 mononucleotide panels). Immunohistochemistry (IHC) was employed to perform mismatch repair protein testing in 1976 samples. RESULTS: We collected 2572 patients with CRC and GC. The National Cancer Institute (NCI) panel failed to detect 13 cases. Of the 2559 cases that received results from all three panels, 2544 showed consistent results. In the remaining 15 cases, 9 showed discrepancies between MSI-H and MSI-L, and 6 showed discrepancies between MSI-L and microsatellite stability (MSS). The misdiagnosis rate of MSI-L was significantly lower in two mononucleotide panels than in the NCI panel (12.5% vs 87.5%, p=0.010) in CRC. In patients with GC, only the NCI panel detected three MSI-L cases, while the results of the two mononucleotide panels were one MSI-H and two MSS. Based on their IHC results, the MSI-L misdiagnosis rate of the NCI panel was 33.3%. Furthermore, compared with two mononucleotide panels, the NCI panel had a much lower rate of all loci instability in CRC (90.8% and 90.3% vs 25.2%) and GC (89.5% and 89.5% vs 12.0%). CONCLUSION: In Chinese patients with CRC and GC, the five and six mononucleotide panels have advantages for detecting MSI over the NCI panel.
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BACKGROUND: Activation of MEK5 in many cancers is associated with carcinogenesis through aberrant cell proliferation. In this study, we determined the level of phosphorylated MEK5 (pMEK5) expression in human colorectal cancer (CRC) tissues and correlated it with clinicopathologic data. METHODS: pMEK5 expression was examined by immunohistochemistry in a tissue microarray (TMA) containing 335 clinicopathologic characterized CRC cases and 80 cases of nontumor colorectal tissues. pMEK5 expression of 19 cases of primary CRC lesions and paired with normal mucosa was examined by Western blotting. The relationship between pMEK5 expression in CRC and clinicopathologic parameters, and the association of pMEK5 expression with CRC survival were analyzed respectively. RESULTS: pMEK5 expression was significantly higher in CRC tissues (185 out of 335, 55.2%) than in normal tissues (6 out of 80, 7.5%; P < 0.001). Western blotting demonstrated that pMEK5 expression was upregulated in 12 of 19 CRC tissues (62.1%) compared to the corresponding adjacent nontumor colorectal tissues. Overexpression of pMEK5 in CRC tissues was significantly correlated to the depth of invasion (P = 0.001), lymph node metastasis (P < 0.001), distant metastasis (P < 0.001) and high preoperative CEA level (P < 0.001). Consistently, the pMEK5 level in CRC tissues was increased following stage progression of the disease (P < 0.001). Analysis of the survival curves showed a significantly worse 5-year disease-free (P = 0.002) and 5-year overall survival rate (P < 0.001) for patients whose tumors overexpressed pMEK5. However, in multivariate analysis, pMEK5 was not an independent prognostic factor for CRC (DFS: P = 0.139; OS: P = 0.071). CONCLUSIONS: pMEK5 expression is correlated with the staging of CRC and its expression might be helpful to the TNM staging system of CRC.
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Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/metabolismo , MAP Quinasa Quinasa 5/metabolismo , Western Blotting , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/secundario , Progresión de la Enfermedad , Humanos , Inmunohistoquímica , Análisis por Micromatrices , Invasividad Neoplásica , Fosforilación , Análisis de SupervivenciaRESUMEN
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
The aim of the present study is to explore possible role of miR-221 in the pathogenesis of HCC. Matched HCC and adjacent non-cancerous samples were assayed for the expression of miR-221 and three G1/S transition inhibitors: p27(Kip1), p21(WAF1/Cip1)and TGF-ß1 by in situ hybridization and immunohistochemistry respectively. p27(Kip1) is one of miR-221's proven targets. Real time qRT-PCR was used to investigate miR-221 and p27(Kip1) transcripts in different clinical stages. Western blotting was used to analyze the expression levels of p27(Kip1) protein in different clinical stages. In result, miR-221 and TGF-ß1 are frequently up-regulated in HCC, while p27(Kip1) and p21(WAF1/Cip1) proteins are frequently down-regulated. Moreover, miR-221 and p27(Kip1)'s expression correlated with metastasis and miR-221's expression also correlated with tumor size. Both of p21(WAF1/Cip1)and TGF-ß1's expression correlated with tumor differentiations. miR-221's upregulation and p27(Kip1)'s downregulation were significantly associated with tumor stages and metastasis. In conclusion, miR-221 is important in tumorigenesis of HCC, possibly by specifically down-regulating p27(Kip1), a cell-cycle inhibitor. These results indicate miR-221 as a new therapeutic target in HCC.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroARNs/metabolismo , Adulto , Anciano , Carcinoma Hepatocelular/patología , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Femenino , Humanos , Hibridación in Situ , Hígado/patología , Hígado/fisiología , Hígado/fisiopatología , Neoplasias Hepáticas/patología , Masculino , MicroARNs/genética , Persona de Mediana Edad , Datos de Secuencia MolecularRESUMEN
BACKGROUND: Tissue factor (TF) is emphasized as the promising target in the future targeted therapy strategy for colorectal cancer (CRC). Recent evidence showed that TF expression is under the control of K-ras and p53. However, a comprehensive evaluation of TF expression, K-ras status, and p53 mutation has not been systematically analyzed. The aims of this study were to identify the percentages of positive TF in CRC patients; analyze the associations of TF expression, K-ras status, and p53 mutation; and evaluate the prognostic value of TF in CRC patients. METHODS: Ninety-six CRC samples were tested for TF expression, p53 mutation, and K-ras status by semiquantitative immunohistochemistry, Western blotting analysis, direct sequencing, and real-time quantitative PCR. Associations were sought with TF expression and clinical outcomes. RESULTS: TF expression was related to clinical stages, tumor differentiation, and tumor size. The positive proportions of TF expression on tumor cells and tumor vascular endothelial cells were 70% and 53% respectively in CRC patients. The positive proportion of TF co-expression on both cancer cells and tumor vascular endothelial cells was 40%, compared to an 83% total TF positive proportion in CRC patients. TF expression on CRC appeared to be increased with K-ras and/or p53 mutation(s). Disease-free survival and overall survival were significantly reduced in CRC patients with high TF expression. CONCLUSIONS: TF may participate in both K-ras and p53 mutations involved in colorectal carcinogenesis and could be considered as a prognostic indicator for patients CRC.
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Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Regulación hacia Abajo/genética , Mutación/genética , Proteínas Proto-Oncogénicas/genética , Tromboplastina/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteínas ras/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas p21(ras) , Resultado del TratamientoRESUMEN
BACKGROUND: PIK3CA is a high-frequency mutation gene in colorectal cancer, while its prognostic value remains unclear. This study evaluated the mutation tendency, spectrum, prognosis power and predictive power in cetuximab treatment of PIK3CA in Chinese CRC cohort. METHODS: The PIK3CA exon 9 and 20 status of 5763 CRC patients was detected with Sanger sequencing and a high-resolution melting test. Clinicopathological characteristics of 5733 patients were analyzed. Kaplan-Meier method and nomogram were used to evaluate the overall survival curve and disease recurrence, respectively. RESULTS: Fifty-eight types of mutations in 13.4% (771/5733) of the patients were detected. From 2014 to 2018, the mutation rate of PIK3CA increased from 11.0% to 13.5%. At stage IV, exon 20 mutated patients suffered shorter overall survival time than wild-type patients (multivariate COX regression analysis, HR = 2.72, 95% CIs = 1.47-5.09; p-value = 0.012). At stage III, PIK3CA mutated patients were more likely to relapse (multivariate Logistic regression analysis, exon 9: OR = 2.54, 95% CI = 1.34-4.73, p = 0.003; exon 20: OR = 3.89, 95% CI = 1.66-9.10, p = 0.002). The concordance index of the nomogram for predicting the recurrence risk of stage III patients was 0.685. After cetuximab treatment, the median PFS of PIK3CA exon 9 wild-type patients (n = 9) and mutant patients (n = 5) did not reach a significant difference (3.6 months vs. 2.3 months, Log-rank test, p-value = 0.513). CONCLUSIONS: We found that PIK3CA mutation was an adverse predictive marker for the overall survival of stage IV patients and recurrence of stage III patients, respectively. Further more, we suggested that PIK3CA exon 9 mutations are not negative predictors of cetuximab treatment in KRAS, NRAS, and BRAF wild-type mCRC patients.
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The objective of this study was to identify proteins that are differentially expressed in the cystic wall tissues of ovarian endometriotic cysts, simple ovarian cysts, and in normal ovarian tissues. Specimens of ovarian endometriotic cyst wall tissue, simple ovarian cyst wall tissue, and normal ovarian tissue (six specimens per group) were collected from patients who received gynecologic surgery, respectively. Differentially expressed proteins related to the ovarian endometriotic cysts were screened by use of isobaric tags for relative and absolute quantitation (iTRAQ) combined with functional annotation and bioinformatics analyses. All differentially expressed proteins related to cysts were validated using immunohistochemistry methods in recurrent and non-recurrent ovarian endometriotic cyst. A total of 359 proteins were identified as up-regulated in ovarian endometriotic cyst groups when compared with both the normal ovary and simple ovarian cyst groups. The levels of 27 proteins were >two-fold higher in the ovarian endometriotic cyst group than that in the other two groups. Of note, the five most significantly upregulated proteins were Charcot-Leyden Crystal Galectin (CLC), Defensin, alpha 1 (DEFA1), S100 calcium-binding protein A9 (S100A9), S100 calcium-binding protein A8 (S100A8), and Ferritin Light Chain (FTL). Immunohistochemistry results showed that the changes of S100A9 and S100A8 were consistent with the results shown by iTRAQ. However, no similarity of CLC, DEFA1, and FTL proteins was found between iTRAQ and immunohistochemistry. The ratio of patients with abnormally high S100A9 and S100A8 expression in the recurrent ovarian endometriotic cyst group was significantly higher than that in the non-recurrent group (P < 0.05). Our data identify differentially expressed proteins S100A9 and S100A8, and suggest they may serve as novel molecular markers to predict postoperative recurrence of an ovarian endometriotic cysts.Abbreviations: iTRAQ: isobaric tags for relative and absolute quantitation; HPRD: Human Protein Reference Database; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; EM: Endometriosis; COX-2: cyclooxyenase-2; NF-kB: nuclear factor kappa-B; PR-B: progesterone receptor type B.
Asunto(s)
Endometriosis/metabolismo , Quistes Ováricos/metabolismo , Adulto , Biomarcadores/metabolismo , Biología Computacional , Endometriosis/complicaciones , Femenino , Perfilación de la Expresión Génica , Humanos , Quistes Ováricos/etiología , Recurrencia , Adulto JovenRESUMEN
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: Colorectal cancer (CRC) patients with different molecular phenotypes, including microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS gene, vary in treatment response and prognosis. However, molecular phenotyping under adequate quality control in a community-based setting may be difficult. We aimed to build the nomograms based on easily accessible clinicopathological characteristics to predict molecular phenotypes. METHODS: Three hundred and six patients with pathologically confirmed stage I-IV CRC were included in the cohort. The assays for MSI, CIMP, and mutations in BRAF and KRAS gene were performed using resected tumor samples. The candidate predictors were identified from clinicopathological variables using multivariate Logistic regression analyses to construct the nomograms that could predict each molecular phenotype. RESULTS: The incidences of MSI, CIMP, BRAF mutation and KRAS mutation were 25.3% (72/285), 2.5% (7/270), 3.4% (10/293), and 34.8% (96/276) respectively. In the multivariate Logistic analysis, poor differentiation and high neutrophil/lymphocyte ratio (NLR) were independently associated with MSI; poor differentiation, high NLR and high carcinoembryonic antigen/tumor size ratio (CSR) were independently associated with CIMP; poor differentiation, lymphovascular invasion and high CSR were independently associated with BRAF mutation; poor differentiation, proximal tumor, mucinous tumor and high NLR were independently associated with KRAS mutation. Four nomograms for MSI, CIMP, BRAF mutation and KRAS mutation were developed based on these independent predictors, the C-indexes of which were 61.22% (95% CI: 60.28-62.16%), 95.57% (95% CI: 95.20-95.94%), 83.56% (95% CI: 81.54-85.58%), and 69.12% (95% CI: 68.30-69.94%) respectively. CONCLUSION: We established four nomograms using easily accessible variables that could well predict the presence of MSI, CIMP, BRAF mutation and KRAS mutation in CRC patients.