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Mounting evidence indicate that cuproptosis, a novel form of programmed cell death, contributes to cancer development and progression. However, a comprehensive analysis regarding the expressions, functions, and regulatory network of cuproptosis-related genes is still lacking. In the present work, cuproptosis-related genes, upstream miRNAs and lncRNAs, and clinical data of breast cancer from TCGA database were analyzed by R language including Cox regression analysis, correlation calculation, ROC curve construction, and survival evaluation, and were further verified by public-available databases. Chemosensitivity and immune infiltration were also evaluated by online tools. SLC31A1 was significantly increased in breast cancer samples than those in normal tissues. SLC31A1 was negatively related to a favorable outcome in breast cancer, and the AUC value increased with the prolongation of follow-up time. LINC01614 and miR-204-5p were potential upstream regulators of SLC31A1. Moreover, SLC31A1 was significantly positively correlated with different immune cells infiltration, immune cell biomarkers, and immune checkpoints in breast cancer. SLC31A1 was a potential cuproptosis-related gene in breast cancer, which was significantly upregulated and was able to predict diagnosis, prognosis, chemosensitivity, and immune infiltration. LINC01640/miR-204-5p/SLC31A1 might be a significant and promising axis during cuproptosis in breast cancer.
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Apoptosis , Neoplasias de la Mama , Transportador de Cobre 1 , MicroARNs , ARN Largo no Codificante , Bases de Datos Factuales , Lenguaje , MicroARNs/genética , ARN Largo no Codificante/genética , Cobre , Humanos , Neoplasias de la Mama/genética , Transportador de Cobre 1/genéticaRESUMEN
BACKGROUND: Breast cancer (BCa) is a major challenge for women's health worldwide. Ferroptosis is closely related to tumorigenesis and cancer progression. However, the prognostic value of ferroptosis-related genes in BCa remains unclear, and more accurate prognostic models are urgently needed. METHODS: Gene expression profiles and clinical information of BCa patients were collected from public databases. LASSO and multivariate Cox regression analysis were utilized to construct the prognostic gene signature. Kaplan-Meier plotter, receiver operating characteristic (ROC) curves, and nomogram were used to validate the prognostic value of the gene signature. Gene set enrichment analysis was performed to explore the molecular functions and signaling pathways. RESULTS: Differentially expressed ferroptosis-related genes between BCa samples and normal tissues were obtained. A novel five-gene signature including BCL2, SLC40A1, TFF1, APOOL, and PRAME was established for prognosis prediction. Patients stratified into high-risk or low-risk group displayed significantly different survival. Kaplan-Meier and ROC curves showed a good performance for survival prediction in different cohorts. Biological function analysis revealed that the five-gene signature was associated with cancer progression, immune infiltration, immune response, and drug resistance. Nomogram including the five-gene signature was established. CONCLUSION: A novel five ferroptosis-related gene signature and nomogram could be used for prognostic prediction in BCa.
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Neoplasias de la Mama , Ferroptosis , Humanos , Femenino , Neoplasias de la Mama/genética , Pronóstico , Ferroptosis/genética , Nomogramas , Carcinogénesis , Antígenos de NeoplasiasRESUMEN
BACKGROUND: Neutrophil extracellular traps (NETs) are considered significant contributors to cancer progression, especially metastasis. However, it is still unclear whether NETs are involved in hepatitis B virus (HBV)-related hepatocarcinogenesis and have potential clinical significance during evaluation and management for hepatocellular carcinoma (HCC). In this study, we aimed to investigate the functional mechanism of NETs in HBV-related hepatocarcinogenesis and their clinical significance. METHODS: A total of 175 HCC patients with and without HBV infection and 58 healthy controls were enrolled in this study. NETs were measured in tissue specimens, freshly isolated neutrophils and blood serum from these patients, and the correlation of circulating serum NETs levels with malignancy was evaluated. The mechanism by which HBV modulates NETs formation was explored using cell-based studies. In addition, in vitro and in vivo experiments were further performed to clarify the functional mechanism of NETs on the growth and metastasis of HCC. RESULTS: We observed an elevated level of NETs in blood serum and tissue specimens from HCC patients, especially those infected with HBV. NETs facilitated the growth and metastasis of HCC both in vitro and in vivo, which were mainly dominated by increased angiogenesis, epithelial-mesenchymal transition (EMT)-related cell migration, matrix metalloproteinases (MMPs)-induced extracellular matrix (ECM) degradation and NETs-mediated cell trapping. Inhibition of NETs generation by DNase 1 effectively abrogated the NETs-aroused HCC growth and metastasis. In addition, HBV-induced S100A9 accelerated the generation of NETs, which was mediated by activation of toll-like receptor (TLR4)/receptor for advanced glycation end products (RAGE)-reactive oxygen species (ROS) signaling. Further, circulatory NETs were found to correlate with viral load, TNM stage and metastasis status in HBV-related HCC, and the identified NETs could predict extrahepatic metastasis, with an area under the ROC curve (AUC) of 0.83 and 90.3% sensitivity and 62.8% specificity at a cutoff value of 0.32. CONCLUSIONS: Our findings indicated that activation of RAGE/TLR4-ROS signaling by HBV-induced S100A9 resulted in abundant NETs formation, which subsequently facilitated the growth and metastasis of HCC cells. More importantly, the identified circulatory NETs exhibited potential as an alternative biomarker for predicting extrahepatic metastasis in HBV-related HCC.
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Carcinoma Hepatocelular , Trampas Extracelulares , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Virus de la Hepatitis B/metabolismo , Trampas Extracelulares/metabolismo , Neoplasias Hepáticas/patología , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Receptor Toll-Like 4/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND AND AIMS: The mechanism underlying HCC metastasis remains unclear, many oncogenes are known to regulate this process. However, the role of alternative splicing (AS) in pro-metastatic HCC is poorly understood. APPROACH AND RESULTS: By performing RNA sequencing on nine pairs of primary HCC tissues with extrahepatic metastasis (EHMH) and nine pairs of metastasis-free HCC (MFH) tissues, we depicted the AS landscape in HCC and found a higher frequency of AS events in EHMH compared with MFH. Moreover, 28 differentially expressed splicing regulators were identified in EHMH compared with MFH. Among these, DEAD-box RNA helicase 17 (DDX17) was significantly up-regulated in EHMH and was strongly associated with patient outcome. Functional studies indicated that DDX17 knockout inhibited the degradation of the extracellular matrix, and diminished the invasive ability of HCC cells. A significant reduction in lung metastasis induced by DDX17 deficiency was also demonstrated in a diethylnitrosamine-induced DDX17HKO mouse model. Mechanistically, high DDX17 induced intron 3 retention of PXN-AS1 and produced a transcript (termed PXN-AS1-IR3). The transcript PXN-AS1-IR3 acted as an important promoter of HCC metastasis by inducing MYC transcription activation via recruiting the complex of testis expressed 10 and p300 to the MYC enhancer region, which led to transcriptional activation of several metastasis-associated downstream genes. Finally, the PXN-AS1-IR3 level was significantly higher in serum and HCC tissues with extrahepatic metastasis. CONCLUSIONS: DDX17 and PXN-AS1-IR3 act as important metastatic promoters by modulating MYC signaling, suggesting that DDX17 and PXN-AS1-IR3 may be potential prognostic markers for metastatic HCC.
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Carcinoma Hepatocelular , ARN Helicasas DEAD-box , Neoplasias Hepáticas , MicroARNs , ARN Largo no Codificante , Empalme Alternativo , Animales , Carcinogénesis/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/genética , ARN Helicasas DEAD-box/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/patología , Masculino , Ratones , MicroARNs/genética , Metástasis de la Neoplasia , Oncogenes , Isoformas de Proteínas/genética , Proteínas Proto-Oncogénicas c-myc/genética , ARN Largo no Codificante/genética , Transducción de SeñalRESUMEN
Chronic hepatitis B virus (HBV) infection is a significant public health burden worldwide. HBV covalently closed circular DNA (cccDNA) organized as a minichromosome in nucleus is responsible for viral persistence and is the key obstacle for a cure of chronic hepatitis B (CHB). Recent studies suggest cccDNA transcription is epigenetically regulated by histone modifications, especially histone acetylation and methylation. In the present study, we identified transcriptionally active histone succinylation (H3K122succ) as a new histone modification on cccDNA minichromosome by using cccDNA ChIP-Seq approach. Silent mating type information regulation 2 homolog 7 (SIRT7), as an NAD+-dependent histone desuccinylase, could bind to cccDNA through interaction with HBV core protein where it catalyzed histone 3 lysine 122 (H3K122) desuccinylation. Moreover, SIRT7 acts cooperatively with histone methyltransferase, suppressor of variegation 3-9 homolog 1 (SUV39H1) and SET domain containing 2 (SETD2) to induce silencing of HBV transcription through modulation of chromatin structure. Our data improved the understanding of histone modifications of the cccDNA minichromosome, thus transcriptional silencing of cccDNA may represent a novel antiviral strategy for the prevention or treatment of HBV infection.
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Catálisis , ADN Circular/metabolismo , Histona Metiltransferasas/genética , Histonas/metabolismo , Sirtuinas/metabolismo , ADN Viral/genética , Hepatitis B/prevención & control , Hepatitis B/terapia , Hepatitis B/virología , Virus de la Hepatitis B/patogenicidad , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/prevención & control , Humanos , Sirtuinas/genética , Transcripción Genética/genética , Replicación Viral/genéticaRESUMEN
Exosome-mediated intercellular communication is considered to be an effective mode for malignant cells to transform biological behaviors in stromal cells. However, the mechanisms by which exosomes modulate macrophages within tumor microenvironment remain largely unclear. In this study, we found that both adriamycin-resistant breast cancer (BCa) cells and the corresponding exosomes (A/exo) were capable of inducing macrophages M2 polarization, which promoted the mobility, proliferation, migration and invasion of BCa cells. Since exosomes deliver microRNAs to affect cellular functions in recipient cells, we confirmed that miR-222 was significantly enriched in A/exo and could be successfully transferred to macrophages. Increased miR-222 level was also detected in exosomes derived from plasma and tissues of chemoresistant patients. Moreover, exosomal miR-222 from A/exo polarized M2 macrophages by targeting PTEN and activating Akt signaling pathway, which promoted BCa cells progression in a feed back loop. Co-culture of adriamycin-resistant BCa cells with macrophages in which miR-222 was upregulated or treated with A/exo facilitated tumor growth in vivo. Collectively, our data demonstrated that chemoresistant BCa cells could remodel macrophages within tumor microenvironment by secreting exosomal miR-222, which directly targeted PTEN and caused Akt cascade activation and macrophages M2 polarization. Our findings may provide a foundation for a promising strategy of BCa treatment by targeting exosomes or exosomal miR-222.
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Polaridad Celular/fisiología , Exosomas/metabolismo , Macrófagos/metabolismo , MicroARNs/metabolismo , Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Progresión de la Enfermedad , Doxorrubicina , Resistencia a Antineoplásicos , Humanos , Células MCF-7 , Microambiente TumoralRESUMEN
Hepatitis B virus (HBV) infection remains a major health problem worldwide. Sufficient maintenance of the HBV covalently closed circular DNA (cccDNA), which serves as a template for HBV transcription, is responsible for the failure of antiviral therapies. While accumulating evidence suggests that cccDNA transcription is regulated by epigenetic machinery, particularly the acetylation and methylation of cccDNA-bound histone 3 (H3) and histone 4 (H4), the potential contributions of histone succinylation and related host factors remain obscured. Here, by screening a series of succinyltransferases and desuccinylases, we identified KAT2A as an important host factor of HBV transcription and replication. By using HBV-infected cells and mouse models with HBV infection, KAT2A was found to affect the transcriptional activity of cccDNA but did not affect cccDNA production. Mechanism studies showed that KAT2A is mainly located in the nucleus and could bind to cccDNA through interaction with HBV core protein (HBc). Moreover, we confirmed histone H3K79 succinylation (H3K79succ) as a histone modification on cccDNA minichromosome by using the cccDNA ChIP-Seq approach. Importantly, KAT2A silencing specifically reduced the level of cccDNA-bound succinylated H3K79. In conclusion, KAT2A promotes HBV transcription and replication through epigenetic machinery, and our findings may provide new insight into the treatment of HBV infection.
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BACKGROUND: Metastasis from extramammary primary tumor to breast is extremely rare. CASE SUMMARY: A 59-year-old woman with 1-year history of rectal cancer presented with asymptomatic breast mass. At 16 months after the diagnosis of rectal mucinous adenocarcinoma, a breast mass was confirmed by ultrasonography and identified by pathology and immunohistochemistry as a metastasis from the rectal cancer. Treatments included chemotherapy (6 cycles: 300 mg irinotecan on day 1, 4.5 mg raltitrexed on day 2, 450 mg bevacizumab on day 3), radiotherapy, and surgical resection. Two years of follow-up examinations (6-months intervals) showed no evidence of recurrence or novel distant metastasis. CONCLUSION: Breast metastasis from rectal carcinoma is a rare secondary malignancy. Final diagnosis can be established by histopathology and immunohistochemistry.
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Neoplasias de la Mama , Carcinoma , Melanoma , Neoplasias del Recto , Neoplasias Cutáneas , Neoplasias de la Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Neoplasias del Recto/patología , Neoplasias del Recto/cirugíaRESUMEN
BACKGROUND & AIMS: Current antiviral therapies help keep HBV under control, but they are not curative, as they are unable to eliminate the intracellular viral replication intermediate termed covalently closed circular DNA (cccDNA). Therefore, there remains an urgent need to develop strategies to cure CHB. Functional silencing of cccDNA is a crucial curative strategy that may be achieved by targeting the viral protein HBx. METHODS: We screened 2,000 small-molecule compounds for their ability to inhibit HiBiT-tagged HBx (HiBiT-HBx) expression by using a HiBiT lytic detection system. The antiviral activity of a candidate compound and underlying mechanism of its effect on cccDNA transcription were evaluated in HBV-infected cells and a humanised liver mouse model. RESULTS: Dicoumarol, an inhibitor of NAD(P)H:quinone oxidoreductase 1 (NQO1), significantly reduced HBx expression. Moreover, dicoumarol showed potent antiviral activity against HBV RNAs, HBV DNA, HBsAg and HBc protein in HBV-infected cells and a humanised liver mouse model. Mechanistic studies demonstrated that endogenous NQO1 binds to and protects HBx protein from 20S proteasome-mediated degradation. NQO1 knockdown or dicoumarol treatment significantly reduced the recruitment of HBx to cccDNA and inhibited the transcriptional activity of cccDNA, which was associated with the establishment of a repressive chromatin state. The absence of HBx markedly blocked the antiviral effect induced by NQO1 knockdown or dicoumarol treatment in HBV-infected cells. CONCLUSIONS: Herein, we report on a novel small molecule that targets HBx to combat chronic HBV infection; we also reveal that NQO1 has a role in HBV replication through the regulation of HBx protein stability. LAY SUMMARY: Current antiviral therapies for hepatitis B are not curative because of their inability to eliminate covalently closed circular DNA (cccDNA), which persists in the nuclei of infected cells. HBV X (HBx) protein has an important role in regulating cccDNA transcription. Thus, targeting HBx to silence cccDNA transcription could be an important curative strategy. We identified that the small molecule dicoumarol could block cccDNA transcription by promoting HBx degradation; this is a promising therapeutic strategy for the treatment of chronic hepatitis B.
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Antivirales/administración & dosificación , ADN Circular/metabolismo , Dicumarol/administración & dosificación , Virus de la Hepatitis B/metabolismo , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/antagonistas & inhibidores , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Proteolisis/efectos de los fármacos , Transactivadores/metabolismo , Transcripción Genética/efectos de los fármacos , Proteínas Reguladoras y Accesorias Virales/metabolismo , Animales , ADN Circular/aislamiento & purificación , Modelos Animales de Enfermedad , Células Hep G2 , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/virología , Hepatocitos/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , NAD(P)H Deshidrogenasa (Quinona)/genética , Transfección , Resultado del Tratamiento , Replicación Viral/efectos de los fármacos , Replicación Viral/genéticaRESUMEN
Substantial advance supports that CMTM2 serve as an important performer in physiological and pathological processes. However, very little is clear about the relationship between CMTM2 and HBV-related disorders. Here, for the first time, we explore that whether or not serum CMTM2 is involved in HBV-related diseases. We found that CMTM2 values were significantly lower in patients compared to healthy control (p <0.001), using ELISA assay. Furthermore, serum CMTM2 levels were negatively correlated with HBV DNA levels in CHB patients but not correlated with the serum levels of ALT and AST. Serum CMTM2 concentrations were not correlated with the serum levels of ALT, AST and HBV DNA load in HBLC and HCC patients. In addition, analysis of the ROC curve indicated that CMTM2 levels were significantly associated with the diagnostic value of HBV-related disorders. Finally, downregulation of CMTM2 was observed in HBV-infected cell model. CMTM2 degradation could be attributed to HBx-activated Lys48 (K48)-linked polyubiquitination, which was abolished by treatment with the proteasome inhibitor MG132. HBV infection suppresses CMTM2 expression by activating ubiquitin-proteasome system. Serum CMTM2 levels can be adopted as an effective indicator of the pathogenesis of HBV-related disorders.
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Carcinoma Hepatocelular/sangre , Quimiocinas/sangre , Hepatitis B Crónica/sangre , Cirrosis Hepática/sangre , Neoplasias Hepáticas/sangre , Proteínas con Dominio MARVEL/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Estudios de Casos y Controles , Quimiocinas/genética , Quimiocinas/metabolismo , Femenino , Células Hep G2 , Virus de la Hepatitis B/patogenicidad , Virus de la Hepatitis B/fisiología , Hepatitis B Crónica/complicaciones , Humanos , Cirrosis Hepática/virología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Proteínas con Dominio MARVEL/genética , Proteínas con Dominio MARVEL/metabolismo , Masculino , Persona de Mediana Edad , Ubiquitinación , Replicación Viral , Adulto JovenRESUMEN
BACKGROUND: The evidence for an association between the adiponectin gene (ADIPOQ) polymorphism rs182052 and cancer risk is inconsistent. We performed a meta-analysis to obtain more precise conclusions. METHODS: The PubMed, Embase, and Web of Science databases were searched until July 11, 2019. And seven epidemiology studies were retrieved, including 4,929 cases and 5,625 controls. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated to evaluate the strength of the association. RESULTS: The meta-analysis demonstrated that rs182052 significantly increased the risk of cancer under the allele, homozygote, dominant, and recessive models, based on an overall analysis (A vs. G: OR, 1.09, 95% CI, 1.03-1.15, P=0.003; AA vs. GG: OR, 1.20, 95% CI, 1.07-1.34, P=0.002; AA+GA vs. GG: OR, 1.12, 95% CI, 1.03-1.22, P=0.010; AA vs. GA+GG: OR, 1.12, 95% CI, 1.01-1.23, P=0.025). In the stratified analysis by ethnicity, rs182052 significantly increased the cancer risk in both Asian and Caucasian populations under one or several genetic models. In the stratified analysis by cancer type, rs182052 significantly increased the risk of renal cell carcinoma (RCC) under the five models. CONCLUSIONS: Meta-analysis based on present studies suggests that rs182052 can increase the cancer risk.
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Adiponectina/genética , Neoplasias/genética , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Neoplasias/diagnóstico , Neoplasias/etnología , Medición de Riesgo , Factores de RiesgoRESUMEN
UBE2L3 is a ubiquitin-conjugating protein belonging to the E2 family that consists of 153 amino acid residues. In this study, we found that UBE2L3 was generally upregulated in clinical HCC samples compared to non-tumour samples and that there was a strong association between high UBE2L3 expression and tumour size, clinical grade and prognosis in HCC patients. UBE2L3 depletion inhibited the proliferation and induced the apoptosis of HCC cells. At the molecular level, we observed that UBE2L3 depletion enhanced the protein stability of GSK3ß, thus promoting the expression and activation of GSK3ß. Subsequently, activated GSK3ß phosphorylated p65 and promoted its nuclear translocation to increase the expression of target genes, including PUMA, Bax, Bim, Bad, and Bid. In vivo, knockout of UBE2L3 in HCC cells inhibited tumour growth in orthotopic liver injection nude mouse models. Moreover, inhibition of p65 or GSK3ß significantly restored the effects induced by UBE2L3 knockout in HCC. Together, this study reveals the stimulatory effect of UBE2L3 on HCC cell proliferation, suggesting that UBE2L3 may be an important pro-tumorigenic factor in liver carcinogenesis and a potential therapeutic target of HCC.
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Apoptosis/genética , Carcinoma Hepatocelular/genética , Glucógeno Sintasa Quinasa 3 beta/genética , Neoplasias Hepáticas/genética , Transducción de Señal/genética , Factor de Transcripción ReIA/genética , Enzimas Ubiquitina-Conjugadoras/genética , Animales , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/genética , Humanos , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fosforilación/genética , Regulación hacia Arriba/genéticaRESUMEN
Cell division cycle protein (CDC20) has been observed to be expressed higher in various kinds of human cancers and was associated with poor prognosis. However, studies on role of CDC20 in breast cancer are seldom reported till now, most of which are not systematic and conclusive. The present study was performed to analyze the expression pattern, potential function, and distinct prognostic effect of CDC20 in breast cancer using several online databases including Oncomine, bc-GenExMiner, PrognoScan, and UCSC Xena. To verify the results from databases, we compared the mRNA CDC20 expression in breast cancer tissues and adjacent normal tissues of patients by real-time PCR. We found that CDC20 was expressed higher in different types of breast cancer, comparing with normal tissues. Moreover, the patients with a more advanced stage of breast cancer tended to express higher level CDC20. CDC20 was expressed higher in breast cancer tissues than normal tissues from patients in our hospital, consistent with the results from databases. Estrogen receptor (ER) and progesterone receptor (PR) status were negatively correlated with CDC20 level. Conversely, Scarff-Bloom-Richardson (SBR) grade, Nottingham prognostic index (NPI), epidermal growth factor receptor-2 (HER-2) status, basal-like status, and triple-negative status were positively related to CDC20 expression in breast cancer patients with respect to normal individuals. Higher CDC20 expression correlated with worse survival. Finally, a positive correlation between CDC20 and Targeting protein for Xenopus kinesin-like protein 2 (TPX2) expression was revealed. CDC20 could be considered as a potential predictive indicator for prognosis of breast cancer with co-expressed TPX2 gene.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/mortalidad , Mama/patología , Proteínas Cdc20/metabolismo , Recurrencia Local de Neoplasia/epidemiología , Factores de Edad , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Proteínas Cdc20/análisis , Proteínas de Ciclo Celular/metabolismo , Biología Computacional , Conjuntos de Datos como Asunto , Supervivencia sin Enfermedad , Femenino , Humanos , Proteínas Asociadas a Microtúbulos/metabolismo , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , PronósticoRESUMEN
AIMS: Baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5) plays vital roles in carcinogenesis by influencing cell division and proliferation and by inhibiting apoptosis. However, the prognostic significance of BIRC5 remains unclear in breast cancer. METHODS: BIRC5 expression and methylation status were evaluated using the Oncomine and The Cancer Genome Atlas (TCGA) databases. The relevance between BIRC5 and different clinicopathological features as well as survival information was analyzed using the bc-GenExMiner database and Kaplan-Meier Plotter. BIRC5-drug interaction network was obtained using the Comparative Toxicogenomics Database. RESULTS: Based on the results from databases and own hospital data, BIRC5 was higher expressed in different breast cancer subtypes compared with the matched normal individuals. Hormone receptors were negatively correlated with BIRC5 expression, whereas the Scarff-Bloom-Richardson (SBR) grade, Nottingham Prognostic Index (NPI), human epidermal growth factor receptor-2 (HER-2) status, basal-like status, and triple-negative status were positively related to BIRC5 level in breast cancer samples with respect to normal tissues. High BIRC5 expression was responsible for shorter relapse-free survival, worse overall survival, reduced distant metastasis free survival, and increased risk of metastatic relapse event. BIRC5-drug interaction network indicated that several common drugs could modulate BIRC5 expression. Furthermore, a positive correlation between BIRC5 andcell-division cycle protein 20 (CDC20) gene was confirmed. CONCLUSION: BIRC5 may be adopted as a promising predictive marker and potential therapeutic target in breast cancer. Further large-scale studies are needed to more precisely confirm the value of BIRC5 in treatment of breast cancer.
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Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Biología Computacional , Survivin/genética , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Proteínas Cdc20/genética , Bases de Datos Genéticas , Femenino , Redes Reguladoras de Genes , Humanos , Persona de Mediana Edad , Pronóstico , Medición de Riesgo , Factores de Riesgo , Transcriptoma , Regulación hacia ArribaRESUMEN
GTPase activating proteins (RhoGAPs) serve significant roles in multiple aspects of tumor biology. Genes encoding RhoGAPs (ARHGAP), which switch off Rho-like GTPases, are responsible for breast cancer biogenesis. However, the identification of suitable and novel biomarkers for precision treatment and prognosis remains challenging. The present study aimed to evaluate the expression of ARHGAP family genes in breast cancer and investigate the survival data using the Oncomine, Kaplan-Meier Plotter, bcGenExMiner and cBioPortal online databases. The results demonstrated low expression of ARHGAP6, 7, 10, 14, 19, 23 and 24 and high expression of ARHGAP9, 11, 15, 18 and 30 in patients with breast cancer compared with that in healthy individuals. The survival analysis revealed that low expression levels of ARHGAP6, 7 and 19 were associated with poor relapse-free survival (RFS) and overall survival (OS), whereas high expression levels of ARHGAP9, 15 and 30 were associated with preferable RFS and OS. Metastatic relapse data demonstrated that higher expression of ARHGAP9, 15, 18, 19, 25 and 30 were associated with better prognosis and increased expression of ARHGAP11A and 14 exerted negative effects on patient prognosis. The overlapping genes ARHGAP9, 15, 19 and 30 obtained from these bioinformatics analysis tools exhibited significant association with clinical parameters including age, the presence of estrogen receptor, progesterone receptor and epidermal growth factor receptor-2, Scarff-Bloom-Richardson grade and Nottingham prognostic index. In conclusion, bioinformatics analysis revealed that ARHGAP9, 15, 19 and 30, but not other ARHGAP family genes may be promising targets with prognostic value and biological function for precision treatment of breast cancer.
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BACKGROUND: The rs2057482 polymorphism in the hypoxia inducible factor 1 subunit alpha (HIF1A) gene has been reported to be associated with a risk of several types of cancer, but this association has not yet been definitively confirmed. We performed this meta-analysis to determine whether rs2057482 is associated with overall cancer risk. METHODS: The PubMed, Embase, and Web of Science databases were searched for the potential studies about the association between the rs2057482 and cancer risk. The data of genotype frequencies in cases with cancer and controls were extracted from the selected studies. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated to determine the strength of the associations. RESULTS: The meta-analysis showed an association between the rs2057482 polymorphism and overall cancer risk. However, a stratified analysis of ethnicity did not show any significant association between rs2057482 and cancer risk in the Asian population. CONCLUSIONS: The rs2057482 polymorphism was associated with decreased overall cancer risk, based on the currently available studies. However, this conclusion needs verification by further well-designed epidemiology studies that examine different cancer types and more subjects.
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Alelos , Predisposición Genética a la Enfermedad , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neoplasias/genética , Polimorfismo de Nucleótido Simple , Estudios de Asociación Genética , Genotipo , Humanos , Oportunidad Relativa , Sesgo de PublicaciónRESUMEN
Background: Resistance to docetaxel is a major obstacle to effective treatment of breast cancer. Exosomal microRNAs (miRNAs) have recently been introduced in cell-to-cell transmission of chemoresistance between heterogeneous populations of tumor cells with diverse drug sensitivity. However, a systematic evaluation of the exosomal miRNA signature remains largely unclear. Method: miRNA expression profiles in exosomes from docetaxel-resistant (D/exo) and parental sensitive breast cancer cells (S/exo) were assessed using microarray. Bioinformatics analysis was performed to predict target genes of the dysregulated miRNAs and to uncover their potential roles in chemoresistance formation. Signaling pathways, gene ontology terms, transcription factors, protein-protein interactions, and hub genes were also constructed. Results: The selected exosomal miRNAs could modulate target genes responsible for MAPK, TGF-beta, Wnt, mTOR, and PI3K/Akt signaling pathways. Function enrichment analysis revealed the involvement of target genes in transcription regulation, protein phosphorylation, kinase activity, and protein binding. Enriched transcription factors including SP1, SP4, and EGR1 were obtained and a protein-protein interaction network was established. The hub genes for up-expressed and down-expressed exosomal miRNAs such as CCND1 and PTEN were identified. Conclusion: This bioinformatics study provides a comprehensive view of the function of dysregulated exosomal miRNAs, and may help us to understand exosome-mediated resistance transmission and overcome docetaxel resistance in future breast cancer therapy.
RESUMEN
Resistance to doxorubicin (DOX) is the most common clinical problem in breast cancer therapy, and the underlying molecular mechanism remains to be investigated. MicroRNAs (miRNAs) exhibit important regulatory functions in various malignant tumors including breast cancer. The aim of the present study was to find the relationship between miR-222 and DOX resistance. We found that miR-222 was highly expressed in patients' serum and DOX-resistant cell line MCF-7-R and that miR-222 could promote proliferation and migration of breast cancer cells. Our results also showed that inhibition of miR-222 in MCF-7-R significantly increased Bcl-2 interacting mediator (Bim) expression both in mRNA and protein levels by using quantitative real-time PCR (qRT-PCR) and Western blot. MTT and flow cytometry suggested that lower expressed miR-222 enhanced apoptosis and decreased IC50 of MCF-7-R cells. Conversely, in MCF-7 cells transfected with miR-222 mimics, up-regulation of miR-222 was associated with decreased Bim level accompanied by less apoptosis and higher IC50 Moreover, miR-222 inhibitors reversed DOX resistance via miR-222-Bim-caspase pathway. Collectively, these data first elucidated that miR-222 could function as an oncogene and was able to reduce the sensitivity of breast cancer cells to DOX through miR-222-Bim-caspase pathway, which provided a potential target to increase DOX sensitivity in clinical breast cancer treatment.
Asunto(s)
Neoplasias de la Mama/metabolismo , Doxorrubicina/farmacología , Resistencia a Antineoplásicos , MicroARNs/metabolismo , ARN Neoplásico/metabolismo , Transducción de Señal , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Humanos , Células MCF-7 , MicroARNs/genética , ARN Neoplásico/genéticaRESUMEN
BACKGROUND: Tumor abnormal protein (TAP) is now gradually applied for early detection of cancers. The aim of this study was to assess the performance of serum TAP in breast cancer patients with a palpable mass. METHODS: TAP from peripheral blood of 217 breast cancer patients and 222 with benign tumors patients were compared. The relationships between TAP value and clinical parameters of breast cancer patients were analyzed. Receiver operating characteristic curve was employed to identify the diagnostic value of TAP. RESULTS: Higher TAP level was found in breast cancer patients compared with benign patients (P<0.001). TAP was not associated with estrogen receptor, progestogen receptor, her-2 expression, tumor size, and pathological degree, but it was significantly associated with the age, lymph node metastasis, and TNM stage (P=0.023, 0.017, and 0.031, respectively). At a cut-off TAP value of 121 µm2, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 59.45%, 63.96%, 61.72%, 61.74%, and 61.73%, respectively. CONCLUSION: Serum TAP may be used as a biomarker in breast cancer diagnosis, but receiver operating characteristic curve indicates it may be limited by its sensitivity/specificity characteristics.
Asunto(s)
Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Proteínas de Neoplasias/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Curva ROC , Sensibilidad y EspecificidadRESUMEN
NAD(P)H: quinone oxidoreductase 1 (NQO1) is an antioxidant enzyme which is associated with poor prognosis in human breast, colon, lung and liver cancers. However, the molecular mechanisms underlying the pro-tumorigenic function of NQO1 remains unclear. This study investigated the function of NQO1 in the context of hepatocellular carcinoma (HCC) development. We found that NQO1 was frequently up-regulated in human liver cancer, and its high expression level was correlated with the tumor stage and low survival rate of HCC patients. Loss-of-function of NQO1 inhibited growth in HCC cells with increased apoptosis in vitro, and suppressed orthotopic tumorigenicity in vivo. Mechanistically, high level of NQO1 in HCC cells enhanced protein stability of X-linked inhibitor of apoptosis protein (XIAP) by increasing its phosphorylation at Ser 87. Reintroduction of wile type XIAP and the phospho-mimic mutants XIAPS87D significantly reversed NQO1 knock-down/out induced growth inhibition and apoptosis. In mouse model with orthotopically implanted hepatocarcinoma, NQO1 suppression and NQO1 inhibitor suppressed tumor growth and induced apoptosis. NQO1 plays an important role in sustaining HCC cell proliferation and may thus act as a potential therapeutic target in HCC treatment.