RESUMEN
AIMS: This study aimed to identify mechanisms of drug resistance to the combination of vemurafenib, irinotecan, and cetuximab (VIC) in BRAFV600E metastatic colorectal cancer (mCRC). METHODS: Forty-one patients with BRAFV600E mCRC from July 2018 and June 2020 were evaluated, with tissue and/or plasma samples collected. We profiled tissue and plasma samples using whole-exome sequencing and targeted sequencing of 425 cancer-relevant genes. Clinical cohort analysis from published studies was performed to consolidate our findings. RESULTS: BRAF mutant in baseline plasma and its dynamics are significantly associated with VIC-related response, and concurrent RNF43 mutation significantly sensitises tumour to VIC treatment. VIC resistance frequently involves genes in PI3K, MAPK pathway, and several novel resistance mechanisms such as TGFBR2 and SMAD4 mutations, and copy-number gains in PTK2, MYC, and GATA6 have been identified. We also firstly describe acquired altered genes in DNA damaging repair pathway, occurring in 33 % of patients after VIC treatment, and particularly, patients with this pre-treatment resistance subclones developed inferior responses, along with higher tumour mutation burden both at baseline and progression plasma. CONCLUSION: Analysis of ctDNA can provide novel insights into molecular resistance mechanisms to VIC in BRAFV600E mCRC patients, allowing accurate guidance for clinicians in personalised treatment strategies.
Asunto(s)
ADN Tumoral Circulante , Neoplasias Colorrectales , Resistencia a Antineoplásicos , Humanos , Cetuximab/farmacología , Cetuximab/uso terapéutico , ADN Tumoral Circulante/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Irinotecán/farmacología , Irinotecán/uso terapéutico , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Vemurafenib/uso terapéuticoRESUMEN
Erratum to: Breast Cancer Res Treat (2012),134:549560,DOI 10.1007/s10549-012-2080-y. In the original publication of the article, Fig. 5c was published incorrectly. The authors apologize for this error and the correct Fig. 5c is given below.
RESUMEN
Background: Transmembrane E3 ubiquitin ligase (RNF43) mutations are present in approximately 6-18% of colorectal cancers (CRC) and could enhance Wnt/ß-catenin signaling, which is emerging as a promising therapeutic target. This study aims to investigate the clinical and molecular characteristics and potential heterogeneity of RNF43-mutant CRC. Methods: A total of 78 patients with RNF43-mutant CRC were enrolled from July 2013 to November 2022. Demographic data, clinical characteristics, treatment regimens used, and survival outcomes were collected and analyzed. Results: Our study uncovered that patients with RNF43 mutations in the N-terminal domain (NTD; n = 50) exhibited shorter overall survival (OS; median months, 50.80 versus not reached; p = 0.043) compared to those in the C-terminal domain (CTD; n = 17). Most RNF43 mutations in NTD had positive primary lymph node status, low tumor mutation burden (TMB-L), and correlated with proficient mismatch repair (pMMR)/microsatellite stable (MSS) status. By contrast, RNF43 mutations in CTD were significantly enriched in deficient MMR (dMMR)/microsatellite instability (MSI-H) tumors with high TMB (TMB-H). N-terminal RNF43-mutated tumors harbored a hotspot variant (RNF43 R117fs), which independently predicted a significantly worse outcome in pMMR/MSS CRC with a median OS of 18.9 months. Patients with RNF43 mutations and the BRAF V600E alterations demonstrated sensitivity to BRAF/EGFR inhibitors. Moreover, we observed that pMMR/MSS patients with RNF43 R117fs mutation had a higher incidence of stage IV, ⩾2 metastatic sites, low TMB, and none of them received PD-1/PD-L1 inhibitor therapy. Conclusion: Our findings provide the first evidence that RNF43 mutations in NTD and the R117fs variant correlate with a poorer prognosis in CRC patients, providing strategies for Wnt-targeted therapy to improve clinical efficacy.
RESUMEN
The accumulation of an intratumoral CD4(+) interleukin-17-producing subset (Th17) of tumor-infiltrating lymphocytes (TILs) is a general characteristic in many cancers. The relationship between the percentage of Th17 cells and clinical prognosis differs among cancers. The mechanism responsible for the increasing percentage of such cells in NPC is still unknown, as is their biological function. Here, our data showed an increase of Th17 cells in tumor tissues relative to their numbers in normal nasopharynx tissues or in the matched peripheral blood of NPC patients. Th17 cells in tumor tissue produced more IFNγ than did those in the peripheral blood of matched NPC patients and healthy controls. We observed high levels of CD154, G-CSF, CXCL1, IL-6, IL-8, and macrophage inhibitory factor (MIF) out of 36 cytokines examined in tumor tissue cultures. MIF promoted the generation and recruitment of Th17 cells mediated by NPC tumor cells in vitro; this promoting effect was mainly dependent on the mammalian target of rapamycin pathway and was mediated by the MIF-CXCR4 axis. Finally, the expression level of MIF in tumor cells and in TILs was positively correlated in NPC tumor tissues, and the frequency of MIF-positive TILs was positively correlated with NPC patient clinical outcomes. Taken together, our findings illustrate that tumor-derived MIF can affect patient prognosis, which might be related to the increase of Th17 cells in the NPC tumor microenvironment.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Interleucina-17/biosíntesis , Oxidorreductasas Intramoleculares/biosíntesis , Factores Inhibidores de la Migración de Macrófagos/biosíntesis , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/mortalidad , Proteínas de Neoplasias/biosíntesis , Células Th17/metabolismo , Microambiente Tumoral , Adulto , Citocinas/biosíntesis , Citocinas/inmunología , Supervivencia sin Enfermedad , Femenino , Humanos , Interleucina-17/inmunología , Oxidorreductasas Intramoleculares/inmunología , Factores Inhibidores de la Migración de Macrófagos/inmunología , Masculino , Neoplasias Nasofaríngeas/inmunología , Neoplasias Nasofaríngeas/patología , Proteínas de Neoplasias/inmunología , Receptores CXCR4/inmunología , Receptores CXCR4/metabolismo , Tasa de Supervivencia , Células Th17/inmunología , Células Th17/patología , Técnicas de Cultivo de TejidosRESUMEN
ULK1 plays an important role in autophagy which is widely involved in the development of breast cancer. However, the function and expression of ULK1 in human breast cancer is still scarcely explored. In this study, we showed that the mRNA and protein levels of ULK1 decreased in 10 of 14 (71.4 %) breast cancer tissues, compared with matched normal tissues. Furthermore, immunohistochemical staining of ULK1 was performed on the tissue microarray containing 298 non-metastatic invasive breast primary cancer tissues and 73 matched adjacent noncancerous tissues. 70.1 % breast cancer specimens displayed none to weak staining of ULK1, however, 78.1 % adjacent noncancerous specimens showed moderate to strong staining of ULK1. Statistical analysis revealed that ULK1 expression was negatively correlated with tumor size (r = -0.176, P = 0.002), lymph node status (r = -0.115, P = 0.048), and pathological stage (r = -0.177, P = 0.002). The log-rank test showed that patients with lower level of ULK1 had a significant shorter distant metastasis-free survival time (P = 0.008) and cancer-related survival time (P = 0.008). Multivariate Cox regression analysis found that ULK1 expression was recognized as an independent prognostic factor (P = 0.034). In addition, a significant positive correlation between expression of ULK1 and LC3A (r = 0.401, P < 0.001), and a significant negative correlation between expression of ULK1 and p62 (r = -0.226, P < 0.001) were observed in our breast cancer cohort. These findings suggest that decreased expression of ULK1 is associated with breast cancer progression, together with closely related to decreased autophagic capacity. ULK1 also may be used as a novel prognostic biomarker for breast cancer patients.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Expresión Génica , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Autofagia , Homólogo de la Proteína 1 Relacionada con la Autofagia , Biomarcadores de Tumor/genética , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/secundario , Carcinoma Ductal de Mama/cirugía , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Estimación de Kaplan-Meier , Análisis Multivariante , Pronóstico , Modelos de Riesgos Proporcionales , Proteínas Serina-Treonina Quinasas/genética , Proteína Sequestosoma-1 , Estadísticas no ParamétricasRESUMEN
BACKGROUND: This study was conducted to investigate the effect of alpha-fetoprotein (AFP) ratio on the prognosis of AFP-positive hepatocellular carcinoma (HCC) patients after hepatectomy. METHODS: We retrospectively included 879 HCC patients with AFP-positive who underwent hepatectomy from February 2012 to October 2017 and randomly divided into training cohort and validation cohort. AFP ratio was equal to the AFP level within one week before hepatectomy to AFP level within 20-40 days after surgery. The end point of follow-up was disease-free survival (DFS) and overall survival (OS). RESULTS: AFP ratio was not associated with clinical characteristics in training cohort and validation cohort. According to the X-tile software, the optimum cut-off point was 17.8 for AFP ratio. Significant differences between AFP ratio high and AFP ratio low were observed in DFS and OS in both cohort (p < 0.05). Kaplan-Meier curves and receiver-operating curves were showed that AFP ratio was better than AFP level preoperation in predicting the prognosis of AFP-positive HCC patients after hepatectomy. The multivariate analysis demonstrated that AFP ratio was a significant independent risk factor for both OS and DFS in HCC patients with AFP-positive. CONCLUSIONS: AFP ratio might be a prognosis predictor for HCC patients with AFP-positive after hepatectomy.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patología , Hepatectomía , Humanos , Neoplasias Hepáticas/patología , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , alfa-Fetoproteínas/análisisRESUMEN
Zinc finger protein 154 (ZNF154) is hypermethylated at the promoter in many epithelial-derived solid tumors. However, its methylation status and function in esophageal squamous carcinoma (ESCC) are poorly understood. We found that the ZNF154 promoter is hypermethylated in ESCC and portends poor prognosis. In addition, ZNF154 functions as a tumor suppressor gene (TSG) in ESCC, and is downregulated by promoter hypermethylation. We established a targeted demethylation strategy based on CRISPR/dCas9 technology and found that the hypermethylation of ZNF154 promoter repressed ZNF154 induction, which in turn promoted the proliferation and migration of ESCC cells in vitro and in vivo. Finally, high-throughput CUT&Tag analysis, GEPIA software and qPCR were used to revealed the role of ZNF154 as a transcription factor to upregulate the expression of ESCC-associated tumor suppressor genes. Taken together, hypermethylation of the ZNF154 promoter plays an important role in the development of ESCC, and epigenetic editing is a promising tool for inhibiting ESCC cells with aberrant DNA methylation.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasias Glandulares y Epiteliales , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Proliferación Celular/genética , Metilación de ADN/genética , Desmetilación , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Neoplasias Glandulares y Epiteliales/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Prior research has established an electrochemical method based on the differential adsorption capacity of gold surfaces with different methylated DNA degrees and found that this method might be valuable for cancer diagnosis by detecting circulating free DNA methylation. However, further investigation on the underlying mechanism and validation of its diagnostic and prognostic values in a large cohort of malignant tumors was limited. We found that DNA with different methylation levels formed particles of diverse sizes on the gold surface. Hydrophobic bonds played a significant role in the binding process of methylated DNA to the gold surface. The detection condition of an adsorption time of 10 min and temperature of 20 °C was optimal. In a large cohort of plasma samples from the patients with different malignant tumors, as well as normal individuals, we found that the electrochemical detection method based on the differential adsorption capacity of methylated DNA degree on a gold surface could be used as a noninvasive tool for malignant tumor diagnosis and prognostic evaluation. The diagnostic efficiency of this method in malignant tumors was even slightly better than that of the current tumor biomarkers widely used in routine clinical practice (circulating free DNA (cfDNA) vs. carcinoembryonic antigen (CEA), 0.8131 vs. 0.7191 and cfDNA vs. CA19-9, 0.7687 vs. 0.6693).
RESUMEN
BACKGROUND: This study aimed to explore the prognostic value of tumor mutational burden (TMB) combined with smoking status in advanced non-small cell lung cancer (NSCLC) patients who received immune checkpoint inhibitor therapy (anti PD-1/PD-L1 therapy) combined with chemotherapy or anti-angiogenesis therapy. METHODS: We conducted a retrospective analysis of NSCLC patients who underwent next-generation sequencing test (either 295-gene panel NGS or 1021-gene panel NGS) from September 2017 to November 2020. The relationship between TMB and smoking status was investigated. Kaplan-Meier survival analysis was used to compare progression-free survival (PFS) of the NSCLC patients who received combination immunotherapy grouped by TMB value and smoking status. RESULTS: We enrolled 323 cases and 388 cases of NSCLC patients in the 295-gene panel cohort and 1021-gene panel cohort, respectively. Positive correlation between TMB and smoking status was found in lung adenocarcinoma, but not in lung squamous cell carcinoma. Participants with both high TMB and smoking status who received immune checkpoint therapy combined with chemotherapy or anti-angiogenesis therapy had longer PFS than other participants (p < 0.05). CONCLUSIONS: The combination of TMB with smoking status might be a potential predictor for the efficacy of combination immunotherapy in advanced NSCLC.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Neoplasias Pulmonares/tratamiento farmacológico , Fumar/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Pulmonares/fisiopatología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios RetrospectivosRESUMEN
The prognostic heterogeneity in patients with BRAF V600E metastatic colorectal cancer (mCRC) remains poorly defined. Real-world data of 93 BRAF V600E mCRC patients from Sun Yat-sen University Cancer Center were evaluated using the prognostic factors affecting overall survival (OS). Treatment of metastases served as an independent prognosticator, where curative locoregional interventions (LRIs) were associated with superior clinical outcomes (adjusted hazard ratio (HR): 0.46, 95% confidence interval (CI): 0.22-0.98; p = 0.044). The LRIs group showed an improved median OS of 49.4 months versus 18.3 months for the palliative treatments (PTs) group. The median OS of patients with colorectal liver metastasis (CRLM) was significantly prolonged after undergoing LRIs (42.4 vs. 23.7 months; HR: 0.11, 95% CI: 0.01-1.22; p = 0.030), and patients in the LRIs plus liver-limited or lung-limited metastasis (LLM) group benefited more than those in the LRIs plus non-LLM group when compared to the PTs group (LLM from LRIs vs. PTs, HR: 0.16, 95% CI: 0.04-0.68; p = 0.006. Non-LLM from LRIs vs. PTs, HR: 0.47, 95% CI: 0.21-1.05; p = 0.074). In conclusion, we confirmed the positive prognostic value of LRIs in BRAF V600E mCRC, particularly in patients with CRLM or LLM.
Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Mutación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Anciano , Estudios de Cohortes , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Metástasis de la Neoplasia , Modelos de Riesgos ProporcionalesRESUMEN
Expression of caveolin-1 (Cav-1) and extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) and their prognostic significance were analyzed in archive NPC samples. Cav-1 and CD147 were overexpressed in 49.48% (96/194) and 59.39% (117/197) of NPC, respectively. Both Cav-1 and CD147 expression levels correlated significantly with metastasis (p = 0.025 and 0.017, respectively) and a lower 5-year survival rate (p = 0.02 and 0.0009, respectively). In addition, Cav-1 expression levels correlated significantly with local recurrence (p = 0.038). Multivariate Cox regression analysis indicated that combination of high Cav-1 and CD147 expression was a significant, independent prognosis predictor in patients with NPC (HR = 2.135; p = 0.006). Functional studies revealed that overexpression of Cav-1 promoted secretion of MMP-3 and MMP-11 (active) proteins, as well as an increase in the migratory ability of CNE1 and CNE2 cells, while siRNA-mediated silencing of Cav-1 or CD147 led to reduced levels of MMP-3 and MMP-11(active) secretion, and reduced migration capacity of CNE1 and CNE2 cells. We observed a positive correlation between Cav-1 and CD147 expression in NPC (rho = 0.330, p = 0.000), CD147 protein levels were upregulated in Cav-1 overexpressing CNE1 and CNE2 cells, whereas siRNA-mediated silencing of Cav-1 led to the downregulation of CD147 expression. Our results indicate that Cav-1 and CD147 overexpression predict poor NPC prognosis and enhanced tumor cell migration, which is associated with MMP-3 and MMP-11 (active) secretion.
Asunto(s)
Basigina/metabolismo , Caveolina 1/metabolismo , Movimiento Celular , Neoplasias Nasofaríngeas/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Regulación hacia Arriba/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Basigina/genética , Caveolina 1/antagonistas & inhibidores , Caveolina 1/genética , Femenino , Humanos , Immunoblotting , Técnicas para Inmunoenzimas , Metástasis Linfática , Masculino , Metaloproteinasa 11 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Persona de Mediana Edad , Neoplasias Nasofaríngeas/patología , Invasividad Neoplásica , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Análisis de Matrices Tisulares , Células Tumorales Cultivadas , Adulto JovenRESUMEN
Overexpression of miR-155 in nasopharygeal carcinoma (NPC) is partly driven by Epstein-Bar virus infection. However the role of miR-155 in NPC oncogenesis is unclear. This study showed that miR-155 inhibitor could inhibit the cell migration in NPC cell lines. ZDHHC2 was identified as a direct target of miR-155 and downregulation of ZDHHC2 prompted cell migration in NPC. Furthermore, reduced ZDHHC2 expression was associated significantly with metastasis and poor survival of NPC patients. Collectively, inhibition of miR-155 suppresses cell migration in NPC through targeting ZDHHC2. The potential of miR-155 and ZDHHC2 as therapeutic targets in NPC should be further investigated.
RESUMEN
Epigenetic silencing of tumor suppressor genes (TSGs) by promoter methylation can be an early event in the multi-step process of carcinogenesis. Human chromosome 3 contains clusters of TSGs involved in many cancer types including nasopharyngeal carcinoma (NPC), the most common cancer in Southern China. Among ten candidate TSGs identified in chromosome 3 using NotI microarray, ITGA9 and WNT7A could be validated. 5'-aza-2' deoxycytidine treatment restored the expression of ITGA9 and WNT7A in two NPC cell lines. Immunostaining showed strong expression of these genes in the membrane and cytoplasm of adjacent control nasopharyngeal epithelium cells, while they were weakly expressed in NPC tumor cells. The ITGA9 promoter showed marked differentially methylation between tumor and control tissue, whereas no differentially methylation could be detected for the WNT7A promoter. The expression level of ITGA9 in NPC tumors was downregulated 4.9-fold, compared to the expression in control. ITGA9 methylation was detected by methylation specific PCR (MSP) in 56% of EBV positive NPC-cases with 100% specificity. Taken together, this suggests that ITGA9 might be a TSG in NPC that is involved in tumor cell biology. The possibility of using ITGA9 methylation as a marker for early detection of NPC should further be explored.
Asunto(s)
Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Cadenas alfa de Integrinas/genética , Integrinas/genética , Neoplasias Nasofaríngeas/genética , Nasofaringe/metabolismo , Regiones Promotoras Genéticas/genética , Antimetabolitos Antineoplásicos/farmacología , Azacitidina/análogos & derivados , Azacitidina/farmacología , Western Blotting , Carcinoma , Estudios de Casos y Controles , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Decitabina , Humanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Wnt/genéticaRESUMEN
BACKGROUND: Zinc finger, DHHC-type containing 2 (ZDHHC2), originally named as reduced expression associated with metastasis protein (REAM), has been proposed as a putative tumor/metastasis suppressor gene and is often aberrantly decreased in human cancers. However ZDHHC2 expression pattern and its clinical significance have not yet been investigated in gastric adenocarcinoma. METHODOLOGY/PRINCIPAL FINDINGS: Quantitative Real-Time PCR (qRT-PCR) and immunostaining were performed to detect ZDHHC2 expression in gastric adenocarcinoma, and then the correlation between ZDHHC2 expression and clinicpathologic parameters, and patient survival was analyzed. Compared to the adjacent normal tissues, ZDHHC2 expression was significantly reduced in gastric tumor tissues as shown by qRT-PCR and immunostaining. Low expression of ZDHHC2 was observed in 44.7% (211/472) of gastric adenocarcinoma patients, and was associated significantly with lymph node metastasis (p<0.001) and histological grade (p<0.001). Multivariate Cox regression analysis indicated that ZDHHC2 expression had a significant, independent predictive value for survival of gastric cancer patients (HRâ=â0.627, pâ=â0.001). CONCLUSIONS/SIGNIFICANCE: Our data suggest that reduced ZDHHC2 expression is associated with lymph node metastasis and independently predicts an unfavorable prognosis in gastric adenocarcinoma patients.
Asunto(s)
Aciltransferasas/genética , Aciltransferasas/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patología , Regulación hacia Abajo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Análisis de SupervivenciaRESUMEN
BACKGROUND: Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase and often aberrantly expressed in human cancers. However, Syk expression pattern has not yet been investigated in nasopharyngeal carcinoma (NPC). METHODS: Samples of 223 NPC tissues were immunohistochemically stained for Syk expression and survival analysis was then performed. Interaction and co-localization of Syk with Epstein-Barr virus encoded latent membrane protein 2A (LMP2A) was explored. RESULTS: High expression of Syk was detected in 24% of NPC cases, and correlated significantly with T classification, local recurrence, a lower 5-year survival rate, and a lower 5-year disease-free survival (DFS) rate. Syk expression was a significant, independent prognosis predictor for patients with NPC. LMP2A induced Syk expression in NPC and LMP2A high expression correlated with Syk high expression in NPC clinical samples. CONCLUSION: High expression of Syk, which results partly from LMP2A expression in NPC, is associated with tumor recurrence and poor prognosis of patients with NPC.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/patología , Proteínas Tirosina Quinasas/metabolismo , Proteínas de la Matriz Viral/metabolismo , Adulto , Análisis de Varianza , Biopsia con Aguja , Western Blotting , Carcinoma , Estudios de Cohortes , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Inmunoprecipitación , Hibridación in Situ , Péptidos y Proteínas de Señalización Intracelular/genética , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/radioterapia , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Proteínas Tirosina Quinasas/genética , Estudios Retrospectivos , Tasa de Supervivencia , Quinasa Syk , Adhesión del Tejido , Proteínas de la Matriz Viral/genéticaRESUMEN
The role of microRNA-155 (miR-155) has been associated with oncogenesis of several human tumors. However the expression pattern of miR-155 has not been investigated in nasopharyngeal carcinoma (NPC). The present study was to assess miR-155 expression pattern and its possible function in NPC, to identify its targets and evaluate their clinical applications in NPC. MiR-155 was found to be upregulated in two Epstein-Barr virus (EBV) negative NPC derived cell lines CNE1 and TW03, as well as in NPC clinical samples by quantitative Real-time PCR and in situ hybridization detection. EBV encoded LMP1 and LMP2A could further enhance the expression of miR-155 in NPC CNE1 and TW03 cells. JMJD1A and BACH1 were identified as putative targets of miR-155 in a bioinformatics screen. Overexpression of miR-155 downregulated a luciferase transcript fused to the 3'UTR of JMJD1A and BACH1. MiR-155 mimic could downregulate the expression of JMJD1A and BACH1, while miR-155 inhibitor could upregulate JMJD1A expression in NPC cell lines. Moreover, downregulation of JMJD1A was significantly correlated with N stage in TNM classification (pâ=â0.023), a lower five-year survival rate (pâ=â0.021), and a lower five-year disease-free survival rate (pâ=â0.049) of NPC patients. Taken together, up-regulation of miR-155 in NPC is partly driven by LMP1 and LMP2A, and results in downregulation of JMJD1A, which is associated with N stage and poor prognosis of NPC patients. The potential of miR-155 and JMJD1A as therapeutic targets in NPC should be further investigated.
Asunto(s)
Biomarcadores de Tumor/genética , Regulación hacia Abajo/genética , Histona Demetilasas con Dominio de Jumonji/genética , MicroARNs/genética , Regulación hacia Arriba/genética , Proteínas de la Matriz Viral/metabolismo , Adolescente , Adulto , Anciano , Secuencia de Bases , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Carcinoma , Línea Celular Tumoral , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Proteínas del Grupo de Complementación de la Anemia de Fanconi/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Histona Demetilasas con Dominio de Jumonji/metabolismo , Estimación de Kaplan-Meier , Masculino , MicroARNs/metabolismo , Persona de Mediana Edad , Datos de Secuencia Molecular , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/virología , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Adulto JovenRESUMEN
The microRNA miR-125b is dysregulated in various human cancers but its underlying mechanisms of action are poorly understood. Here, we report that miR-125b is downregulated in invasive breast cancers where it predicts poor patient survival. Hypermethylation of the miR-125b promoter partially accounted for reduction of miR-125b expression in human breast cancer. Ectopic restoration of miR-125b expression in breast cancer cells suppressed proliferation, induced G(1) cell-cycle arrest in vitro, and inhibited tumorigenesis in vivo. We identified the ETS1 gene as a novel direct target of miR-125b. siRNA-mediated ETS1 knockdown phenocopied the effect of miR-125b in breast cell lines and ETS1 overexpression in invasive breast cancer tissues also correlated with poor patient prognosis. Taken together, our findings point to an important role for miR-125b in the molecular etiology of invasive breast cancer, and they suggest miR-125b as a potential theranostic tool in this disease.
Asunto(s)
Neoplasias de la Mama/metabolismo , Regulación Neoplásica de la Expresión Génica , MicroARNs/metabolismo , Proteína Proto-Oncogénica c-ets-1/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Línea Celular Tumoral , Proliferación Celular , Metilación de ADN , Femenino , Fase G1 , Perfilación de la Expresión Génica , Humanos , Invasividad Neoplásica , Metástasis de la Neoplasia , Pronóstico , Proto-Oncogenes Mas , Resultado del TratamientoRESUMEN
PURPOSE: Currently, nasopharyngeal carcinoma (NPC) prognosis evaluation is based primarily on the TNM staging system. This study aims to identify prognostic markers for NPC. PATIENTS AND METHODS: We detected expression of 18 biomarkers by immunohistochemistry in NPC tumors from 209 patients and evaluated the association between gene expression level and disease-specific survival (DSS). We used support vector machine (SVM)--based methods to develop a prognostic classifier for NPC (NPC-SVM classifier). Further validation of the NPC-SVM classifier was performed in an independent cohort of 1,059 patients. RESULTS: The NPC-SVM classifier integrated patient sex and the protein expression level of seven genes, including Epstein-Barr virus latency membrane protein 1, CD147, caveolin-1, phospho-P70S6 kinase, matrix metalloproteinase 11, survivin, and secreted protein acidic and rich in cysteine. The NPC-SVM classifier distinguished patients with NPC into low- and high-risk groups with significant differences in 5-year DSS in the evaluated patients (87% v 37.7%; P < .001) in the validation cohort. In multivariate analysis adjusted for age, TNM stage, and histologic subtype, the NPC-SVM classifier was an independent predictor of 5-year DSS in the evaluated patients (hazard ratio, 4.9; 95% CI, 3.0 to 7.9) in the validation cohort. CONCLUSION: As a powerful predictor of 5-year DSS among patients with NPC, the newly developed NPC-SVM classifier based on tumor-associated biomarkers will facilitate patient counseling and individualize management of patients with NPC.