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CircRNA is a kind of covalent head-to-tail looped RNA and plays an important role in tumor development. However, the identification of new potential targetable circRNAs to inhibit cancer development is still a huge challenge. In this study, we found that circEHMT1 inhibited migration and invasion of breast cancer cells. Mechanistically, we identified miR-1233-3p as a target of circEHMT1, and the circEHMT1/miR-1233-3p axis regulated matrix metalloprotease 2 (MMP2) by modulating the transcription factor KrÏppel-like factor 4 (KLF4). In summary, we showed that circEHMT1 has potential as a prognostic factor in breast cancer and played a tumor suppressor role via the circEHMT1/miR-1233-3p/KLF4/MMP2 axis.
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Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição Kruppel-Like/genética , Metaloproteinase 2 da Matriz/genética , MicroRNAs/genética , RNA Circular/genética , Animais , Neoplasias da Mama/patologia , Movimento Celular , Feminino , Humanos , Fator 4 Semelhante a Kruppel , Camundongos Endogâmicos BALB C , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologiaRESUMO
Poly(ADP-ribose) polymerase (PARP)-1 may act in an error-prone pathway called alternative end joining (Alt-EJ) for DNA double-strand break (DSB) repair when nonhomologous end joining is defective. We examined the recruitment of PARP-1 to chromatin in response to radiomimetic agents and the effects of PARP-1 inhibition on DSB repair and recruitment of the meiotic recombination (MRE)-11-double-strand break repair (RAD50) protein-Nijmegen breakage syndrome (NSB)-1 (MRN) complex to the chromatin in Ku70-deficient breast cancer cells. The chromatin-binding affinity of PARP-1 was enhanced in response to neocarzinostatin (NCS) or calicheamicin treatment in the absence of Ku70. PARP-1 inhibition impaired the repair of both NCS-induced DSBs and intron-encoded endonuclease from Physarum polycephalum-induced site-specific DSB. Both fractionation and chromatin immunoprecipitation assays demonstrated that chromatin recruitment of MRN was PARP-1 dependent. These data suggest that PARP-1 is vital for DSB repair in breast cancer cells when Alt-EJ is activated.-Huang, Y., Shao, Q., Luo, X., Yang, D., Zeng, B., Xiang, T., Ren, G., Cheng, Q. Poly(ADP-ribose) polymerase-1 promotes recruitment of meiotic recombination-11 to chromatin and DNA double-strand break repair in Ku70-deficient breast cancer cells.
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CDKN1C, also known as p57kip2, is considered to be a potential tumor suppressor implicated in several kinds of human cancers. However, the current knowledge of CDKN1C in breast cancer remains obscure. In the present study, we demonstrated that CDKN1C was dramatically downregulated in breast cancer compared with normal tissues by using real-time quantitative polymerase chain reaction, western blot and two public data portals: The Cancer Genome Atlas (TCGA) and Oncomine datasets. Moreover, the expression of CDKN1C was correlated with age and tumor size in the TCGA cohort containing 708 cases of breast cancer. Low expression of CDKN1C was significantly associated with poor overall survival (OS) in the TCGA cohort and validated cohort composed of 1402 patients. Multivariate Cox regression analysis indicated that CDKN1C was an independent prognostic factor for worse OS (HRâ¯=â¯1.78, 95% CI: 1.09-2.89, pâ¯=â¯0.020). Furthermore, gene set enrichment analysis (GSEA) revealed that CDKN1C was significantly correlated with gene signatures involving DNA repair, cell cycle, glycolysis, adipogenesis, and two critical signaling pathways mTORC1 and PI3K/Akt/mTOR. In conclusion, our data suggested an essential role of CDKN1C in the tumorgenesis of breast cancer. Targeting CDKN1C may be a promising strategy for anticancer therapeutics.
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Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Carcinogênese/metabolismo , Carcinogênese/patologia , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , China/epidemiologia , Regulação para Baixo , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
The abnormal expression of microRNAs is a key hallmark of breast cancer. Nevertheless, the biological roles of miR-1247-5p in breast cancer remain unknown. In this study, we revealed that miR-1247-5p expression was markedly decreased in breast cancer. It was a valuable diagnostic biomarker for breast cancer with the area under the curve of more than 0.80. Reduced miR-1247-5p expression was significantly correlated with patient age, tumor size, and poor prognosis in The Cancer Genome Atlas cohort including 839 breast cancer patients. Multivariate Cox regression analysis demonstrated that miR-1247-5p was an independent prognostic indicator for overall survival (hazard radio [HR]â¯=â¯1.683, 95% confidence interval [CI]â¯=â¯1.087-2.606, pâ¯=â¯0.020) and recurrence-free survival (HRâ¯=â¯2.496, 95% CIâ¯=â¯1.576-3.951, pâ¯<â¯0.001). Moreover, functional studies showed that overexpression of miR-1247-5p inhibited proliferation and induced apoptosis in breast cancer cells. Bioinformatics analysis and mechanistic investigations revealed that Dishevelled 1 (DVL1) was a direct target of miR-1247-5p. Inhibition of DVL1 by miR-1247-5p resulted in the suppression of Wnt/ß-catenin signaling, whereas overexpression of DVL1 abrogated the miR-1247-5p-mediated effect. These data reveal that miR-1247-5p, as an oncosuppressor in breast cancer, may be a promising prognostic biomarker and therapeutic target.
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Neoplasias da Mama/genética , Proliferação de Células/genética , Proteínas Desgrenhadas/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Via de Sinalização Wnt/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proteínas Desgrenhadas/metabolismo , Regulação para Baixo , Feminino , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Células MCF-7 , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: To determine whether adipocyte-derived lipids could be transferred into breast cancer cells and investigate the underlying mechanisms of subsequent lipolysis and fatty acid trafficking in breast cancer cells. METHODS: A Transwell co-culture system was used in which human breast cancer cells were cultured in the absence or presence of differentiated murine 3 T3-L1 adipocytes. Migration/invasion and proliferation abilities were compared between breast cancer cells that were cultivated alone and those co-cultivated with mature adipocytes. The ability of lipolysis in breast cancer cells were measured, as well as the expression of the rate-limiting lipase ATGL and fatty acid transporter FABP5. ATGL and FABP5 were then ablated to investigate their impact on the aggressiveness of breast cancer cells that were surrounded by adipocytes. Further, immunohistochemistry was performed to detect differential expression of ATGL and FABP5 in breast cancer tissue sections. RESULTS: The migration and invasion abilities of cancer cells were significantly enhanced after co-culture with adipocytes, accompanied by elevated lipolysis and expression of ATGL and FABP5. Abrogation of ATGL and FABP5 sharply attenuated the malignancy of co-cultivated breast cancer cells. However, this phenomenon was not observed if a lipid emulsion was added to the culture medium to substitute for adipocytes. Furthermore, epithelial-mesenchymal transaction was induced in co-cultivated breast cancer cells. That may partially due to the stimulation of PPARß/δ and MAPK, which was resulted from upregulation of FABP5. As evidenced by immunohistochemistry, ATGL and FABP5 also had higher expression levels at the invasive front of the breast tumor, in where the adipocytes abound, compared to the central area in tissue specimens. CONCLUSIONS: Lipid originating from tumor-surrounding adipocytes could be transferred into breast cancer cells. Adipocyte-cancer cell crosstalk rather than lipids alone induced upregulation of lipases and fatty acid transport protein in cancer cells to utilize stored lipids for tumor progression. The increased expression of the key lipase ATGL and intracellular fatty acid trafficking protein FABP5 played crucial roles in this process via fueling or signaling.
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Adipócitos/patologia , Neoplasias da Mama/patologia , Progressão da Doença , Ácidos Graxos/metabolismo , Espaço Intracelular/metabolismo , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Transporte Biológico , Comunicação Celular , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Lipase/metabolismo , Lipólise , Células MCF-7 , CamundongosRESUMO
Therapeutic resistance in cancer remains a dilemma that scientists and oncologists are eager to solve. Despite several preclinical and clinical studies dedicated to overcoming therapeutic resistance, they often do not yield the expected outcomes. This is primarily due to the multifactorial phenomenon of therapeutic resistance. Norcantharidin (NCTD) is an artificial compound derived from cantharidin that has significant anticancer efficacy without incurring serious side effects. Intriguingly, extensive research suggests that NCTD is essential for boosting anticancer efficacy and reversing treatment resistance. This review article presents a full description of how NCTD can effectively overcome cancer resistance to standard treatments such as chemotherapy, radiation, hormone therapy, and targeted therapy. We also discuss the potential prospects and challenges associated with using NCTD as a therapeutic strategy for reversing resistance to cancer therapy. We anticipate that our review will serve as a valuable reference for researchers and clinicians.
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Antineoplásicos , Neoplasias , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Apoptose , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológicoRESUMO
OBJECTIVE: To investigate the diagnostic value of urine luteinizing hormone (ULH) after the triptorelin stimulation test detected by immunochemiluminometric assay (ICMA) in girls with central precocious puberty (CPP). METHODS: The girls with precocious puberty were included. The triptorelin stimulation test at 8:30 a.m. was performed. Two consecutive 12-hour urine samples were collected after the test, defined as the first 12-hour and second 12-hour urine, respectively. ICMA measured ULH. Urine creatinine (Cr) concentration was measured. CPP and peripheral precocious puberty (PPP) were diagnosed by the same pediatric endocrinologist based on clinical symptoms, signs, and progression of clinical development. RESULTS: A total of 97 cases (CPP n=69; PPP n=28) were included, with 12 cases not meeting the receiver operating characteristic analysis criteria. The first and second 12-hour ULH/Cr in the CPP group were higher than those in the PPP group. When the first 12-hour ULH/Cr was≥287.252 IU/mol, the sensitivity and specificity for diagnosing CPP were 87.3% and 90.9%, respectively. When the second 12-hour ULH/Cr was≥152.769 IU/mol, the sensitivity and specificity for diagnosing CPP were 92.1% and 90.9%, respectively. The area under the curve of the first and second 12-hour ULH/Cr were 0.933 and 0.954, respectively. CONCLUSION: The ULH detection method after the triptorelin stimulation test has clinical significance for diagnosing CPP in girls. When blood sampling compliance in girls with precocious puberty is poor, the first 12-hour ULH/Cr≥288 IU/mol (or second 12-hour≥153 IU/mol) after the triptorelin stimulation test can serve as a laboratory indicator for diagnosis of CPP.
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Hormônio Luteinizante , Puberdade Precoce , Pamoato de Triptorrelina , Humanos , Puberdade Precoce/urina , Puberdade Precoce/diagnóstico , Puberdade Precoce/sangue , Puberdade Precoce/tratamento farmacológico , Feminino , Pamoato de Triptorrelina/farmacologia , Criança , Hormônio Luteinizante/sangue , Hormônio Luteinizante/urina , Pré-Escolar , Sensibilidade e EspecificidadeRESUMO
To overcome C797S mutation, the latest and most common resistance mechanism in the clinical treatment of third-generation EGFR inhibitor, a novel series of substituted 6-(2-aminopyrimidine)-indole derivatives were designed and synthesized. Through the structure-activity relationship (SAR) study, compound 11eg was identified as a novel and potent EGFR L858R/T790M/C797S inhibitor (IC50 = 0.053 µM) but had a weak effect on EGFRWT (IC50 = 1.05 µM). 11eg significantly inhibited the proliferation of the non-small cell lung cancer (NSCLC) cells harboring EGFRL858R/T790M/C797S with an IC50 of 0.052 µM. 11eg also showed potent inhibitory activity against other NSCLC cell lines harboring main EGFR mutants. Furthermore, 11eg exhibited much superior activity in arresting cell cycle and inducing apoptosis of NSCLC cells with mutant EGFRC797S. It blocked cellular EGFR signaling. Importantly, 11eg markedly suppressed the tumor growth in in vivo xenograft mouse model with good safety. Additionally, 11eg displayed good microsomal stability. These results demonstrated the potential of 11eg with novel scaffold as a promising lead compound targeting EGFRC797S to guide in-depth structural optimization.
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Long non-coding RNAs (LncRNAs) play essential roles in multiple physiological processes including bone formation. Investigators have revealed that LncRNAs regulated bone formation through various signaling pathways and micro RNAs (miRNAs). However, several problems exist in current research studies on osteogenic LncRNAs, including sophisticated techniques, high cost for in vivo experiment, as well as low homology of LncRNAs between animal model and human, which hindered translational medicine research. Moreover, compared with gene editing, LncRNAs would only lead to inhibition of target genes rather than completely knocking them out. As the studies on osteogenic LncRNA gradually proceed, some of these problems have turned osteogenic LncRNA research studies into slump. This review described some new techniques and innovative ideas to address these problems. Although investigations on osteogenic LncRNAs still have obtacles to overcome, LncRNA will work as a promising therapeutic drug for osteoporosis in the near future.
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MicroRNAs , Osteoporose , RNA Longo não Codificante , Animais , Humanos , RNA Longo não Codificante/genética , Osteogênese/genética , Osteoporose/tratamento farmacológico , Osteoporose/genética , Edição de GenesRESUMO
Background: Polycystic ovary syndrome (PCOS) is a complex, multifactor disorder in women of reproductive age worldwide. Although RNA editing may contribute to a variety of diseases, its role in PCOS remains unclear. Methods: A discovery RNA-Seq dataset was obtained from the NCBI Gene Expression Omnibus database of granulosa cells from women with PCOS and women without PCOS (controls). A validation RNA-Seq dataset downloaded from the European Nucleotide Archive Databank was used to validate differential editing. Transcriptome-wide investigation was conducted to analyze adenosine-to-inosine (A-to-I) RNA editing in PCOS and control samples. Results: A total of 17,395 high-confidence A-to-I RNA editing sites were identified in 3,644 genes in all GC samples. As for differential RNA editing, there were 545 differential RNA editing (DRE) sites in 259 genes with Nucleoporin 43 (NUP43), Retinoblastoma Binding Protein 4 (RBBP4), and leckstrin homology-like domain family A member 1 (PHLDA) showing the most significant three 3'-untranslated region (3'UTR) editing. Furthermore, we identified 20 DRE sites that demonstrated a significant correlation between editing levels and gene expression levels. Notably, MIR193b-365a Host Gene (MIR193BHG) and Hook Microtubule Tethering Protein 3 (HOOK3) exhibited significant differential expression between PCOS and controls. Functional enrichment analysis showed that these 259 differentially edited genes were mainly related to apoptosis and necroptosis pathways. RNA binding protein (RBP) analysis revealed that RNA Binding Motif Protein 45 (RBM45) was predicted as the most frequent RBP binding with RNA editing sites. Additionally, we observed a correlation between editing levels of differential editing sites and the expression level of the RNA editing enzyme Adenosine Deaminase RNA Specific B1 (ADARB1). Moreover, the existence of 55 common differentially edited genes and nine differential editing sites were confirmed in the validation dataset. Conclusion: Our current study highlighted the potential role of RNA editing in the pathophysiology of PCOS as an epigenetic process. These findings could provide valuable insights into the development of more targeted and effective treatment options for PCOS.
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Síndrome do Ovário Policístico , RNA , Humanos , Feminino , RNA/metabolismo , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo , Edição de RNA , Perfilação da Expressão Gênica , Células da Granulosa/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismoRESUMO
BACKGROUND: Caseinolytic protease P (ClpP), which is located on the inner mitochondrial membrane, degrades mitochondrial proteins damaged by oxidative stress. The role of ClpP varies among tumor types. However, the expression pattern and biological functions of ClpP in breast cancer (BC) have not yet been investigated. METHODS: The Cancer Genome Atlas (TCGA) and Kaplan Meier-plotter database were used to analyze the expression level of ClpP in BC tissues, relationships with clinicopathological characteristics, and the influence on the prognosis of BC. Protein and mRNA expression levels of ClpP in BC cell lines and tissues were detected by quantitative real-time PCR, western blot and immunohistochemical (IHC) analyses. The colony formation assay, transwell assay and flow cytometric analysis were performed to assess various functions of ClpP. Western blot analysis was also conducted to determine the mechanism of ClpP. RESULTS: ClpP expression was markedly increased in BC cells and tissues. High expression of ClpP was significantly correlated with the T stage, estrogen receptor (ER) expression, and poor recurrence-free survival (RFS) in TCGA and Kaplan Meier-plotter database. ClpP silencing significantly inhibited proliferation, migration, invasion, and promoted apoptosis of BC cells, which resulted in suppression of the Src/PI3K/Akt signaling pathway. The gain-of-function assay confirmed partial these results.
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BACKGROUND: Circular RNAs (circRNAs) are a special class of noncoding RNAs that are involved in gene regulation and compete with mRNA for miRNA binding sites. The roles of circRNAs in cancer, especially breast cancer (BC), are poorly understood. MATERIALS AND METHODS: The expression levels of circRNA 0001073 (circ-1073) in BC cells (BCCs) and tissues and peritumoural tissues were detected by real-time quantitative reverse transcription-polymerase chain reaction. Kaplan-Meier analysis and receiver operating characteristic curves were used to evaluate relapse-free survival (RFS) and the diagnostic value of circ-1073 for BC, respectively. The biological functions of circ-1073 were determined by cell counting kit-8 assays, colony formation assays, flow cytometry, wound-healing assays, transwell assays, and xenograft model studies. RNA immunoprecipitation assays were conducted to identify the connection between circ-1073 and human antigen R (HuR). RESULTS: Low circ-1073 expression was discovered in BCCs and BC tissues compared with normal mammary epithelial cells and peritumoural tissues, respectively. Circ-1073 downregulation was significantly associated with an unfavourable prognosis, including a shorter RFS, in BC patients. Circ-1073 is a valuable diagnostic biomarker for BC. Circ-1073 overexpression significantly inhibited BCC proliferation and induced apoptosis by increasing Cleaved Caspase-3/9 levels. Moreover, circ-1073 upregulation significantly suppressed cell mobility and epithelial-mesenchymal transition. Notably, xenograft tumour growth was inhibited by the intratumoural injection of nanoparticles containing the circ-1073 plasmid or by circ-1073 overexpression, and this inhibition was accompanied by HuR upregulation. CONCLUSION: Circ-1073 functions as a tumour suppressor in BC, suggesting its potential as a novel therapeutic target in BC.
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BACKGROUND: Rho GTPase-activating protein 10 (ARHGAP10), which catalyzes the conversion of active Rho GTPase to the inactive form, is downregulated in some cancers. However, little is known about ARHGAP10 in breast cancer. METHODS: The transcriptional expression level of ARHGAP10 in breast cancer was analyzed with the data downloaded from The Cancer Genome Atlas (TCGA) and Oncomine, then verified by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) in 30 pairs of breast cancer tissues and the corresponding adjacent normal tissues. ARHGAP10 protein expression was examined by immunohistochemistry (IHC) in 190 breast cancer and 30 corresponding adjacent normal breast tissue samples. The associations between ARHGAP10 expression and clinicopathological characteristics of patients were analyzed, and Kaplan-Meier Plotter was used to assess the relationship between ARHGAP10 and relapse-free survival (RFS). Different expression levels of ARHGAP10 in response to chemotherapy agents were determined by GEO2R online tool. The potential biological functions of ARHGAP10 were analyzed by Gene Set Enrichment Analysis (GSEA) using data downloaded from TCGA. RESULTS: ARHGAP10 mRNA and protein expression was lower in breast cancer tissues than in adjacent normal tissues. Low expression of ARHGAP10 was associated with advanced clinical TNM (cTNM) stage (p b = 0.001) and high Ki-67 index (p = 0.015). Low expression of ARHGAP10 indicated worse RFS (p = 0.0015) and a poor response to chemotherapy (p = 0.006). GSEA results showed that ARHGAP10 was involved in signaling pathways including protein export, nucleotide excision repair, base excision repair, focal adhesion, JAK-STAT pathway and the actin cytoskeleton.
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BACKGROUND: Recently, emerging evidence has indicated crucial roles for long noncoding RNAs (lncRNAs) in breast cancer (BC) development and progression. Our study aimed to investigate the clinical significance of LINC01089 in patients with BC and to determine its biological functions and underlying molecular mechanisms. MATERIALS AND METHODS: Correlations between LINC01089 expression and the clinicopathological characteristics of BC patients were assessed using chi-square tests. The Kaplan-Meier method was used to produce survival curves. The clinical risk characteristics associated with the overall survival and recurrence-free survival of patients with BC were estimated using univariate and multivariate Cox regression analyses. Several methods were used to determine the expression profile, biological functions and underlying mechanisms of LINC01089 in BC, including cell proliferation assays, colony formation assays, flow cytometry, transwell assays, wound healing assays, quantitative real-time polymerase chain reaction and Western blotting. RESULTS: LINC01089 was downregulated in BC tissues and cell lines. Low LINC01089 expression was significantly correlated with age (P=0.026), lymph node metastasis (P=0.003), and poor prognosis of patients with BC. According to the multivariate Cox regression analysis results, LINC01089 was an independent prognostic indicator of overall survival (P=0.032) and recurrence-free survival (P=0.014). Functional studies revealed significant decreases in the proliferation, migration, and invasion of tumor cells overexpressing LINC01089, and EGF could reverse above effects of LINC01089 on BC cells. Additionally, increased LINC01089 expression promoted apoptosis and cell cycle arrest at G0/G1 phase, accompanied by decreased expression of the key cell cycle regulators CDK4 and CDK6. Loss-of-function assays confirmed partial results. Mechanistically, LINC01089 blocked the Wnt/ß-catenin pathway and the expression of downstream target genes by inhibiting ß-catenin expression at the transcriptional level. CONCLUSION: Based on our results, LINC01089 functions as a tumor suppressor and potentially represents a novel prognostic indicator and therapeutic target in BC.
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BACKGROUND: The microRNAs (miRNAs) have been validated as prognostic markers in many cancers. The aim of this study was to identify new miRNA prognostic biomarkers in endometrial cancer (EC) and to develop an expression-based miRNA signature to provide survival risk prediction for EC patients. METHODS: From TCGA database, the miRNA datasets of EC and clinical information were downloaded in April 2018. Using univariate and multivariate Cox regression analyses identify prognostic factors. Using area under the curve (AUC) of receiver operating characteristic (ROC) curve assess the sensitivity and specificity of prognostic model. RESULTS: 530 patients were randomly divided into training set and testing set. Among 561 differentially expressed miRNAs, 4 miRNAs (miR-4758, miR-876, miR-142, miR-190b) were demonstrated to be predictive biomarkers of overall survival (OS) for EC patients in training set. Based on the risk score of 4-miRNA model, patients in the training set were divided into high-risk and low-risk groups with significantly different OS. This 4-miRNA model was validated in testing and entire set. The AUC for the ROC curves in the entire set was 0.704. Meanwhile, multivariate Cox regression combined with other traditional clinical parameters indicated that the 4-miRNA model can be used as an independent OS prognostic factor. Functional enrichment analysis revealed that these miRNAs are involved in biological processes and pathways that are closely related to cancer. CONCLUSION: A robust 4-miRNA signature as an independent prognostic factor for OS in EC patients was established.
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Biomarcadores Tumorais/genética , Neoplasias do Endométrio/genética , MicroRNAs/genética , Adulto , Idoso , Área Sob a Curva , Biomarcadores Tumorais/sangue , China , Neoplasias do Endométrio/mortalidade , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Estimativa de Kaplan-Meier , MicroRNAs/sangue , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Taxa de SobrevidaRESUMO
Alterations in the ubiquitin-proteasome system (UPS) and UPS-associated proteins have been implicated in the development of many human malignancies. In this study, we investigated the expression profiles of 797 UPS-related genes using HiSeq data from The Cancer Genome Atlas and identified that PSMD2 was markedly upregulated in breast cancer. High PSMD2 expression was significantly correlated with poor prognosis. Gene set enrichment analysis revealed that transcriptome signatures involving proliferation, cell cycle, and apoptosis were critically enriched in specimens with elevated PSMD2. Consistently, PSMD2 knockdown inhibited cell proliferation and arrested cell cycle at G0/G1 phase in vitro, as well as suppressed tumor growth in vivo. Rescue assays demonstrated that the cell cycle arrest caused by silencing PSMD2 partially resulted from increased p21 and/or p27. Mechanically, PSMD2 physically interacted with p21 and p27 and mediated their ubiquitin-proteasome degradation with the cooperation of USP14. Notably, intratumor injection of therapeutic PSMD2 small interfering RNA effectively delayed xenograft tumor growth accompanied by p21 and p27 upregulation. These data provide novel insight into the role of PSMD2 in breast cancer and suggest that PSMD2 may be a potential therapeutic target.
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Neoplasias da Mama/patologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Fator 2 Associado a Receptor de TNF/metabolismo , Animais , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Injeções Intralesionais , Estimativa de Kaplan-Meier , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Complexo de Endopeptidases do Proteassoma/metabolismo , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Fase de Repouso do Ciclo Celular , Fator 2 Associado a Receptor de TNF/genética , Ubiquitina Tiolesterase/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Recent studies suggested the globin family member cytoglobin (CYGB) as a potential tumor suppressor; however, the mechanism by which CYGB suppresses cancer is elusive. We investigated the role and mechanism of CYGB in suppressing breast cancer. METHODS: CYGB expression was examined by reverse transcription PCR, quantitative reverse transcription PCR and open database analysis. Promoter methylation was examined by methylation-specific PCR. Metabolomics and proteomics were analyzed by gas chromatography-mass spectrometry and isobaric tags for relative and absolute quantitation, respectively. The effects and mechanisms of ectopic CYGB expression in breast cancer cells were assessed with molecular biological and cellular approaches in vitro and with a xenograft tumor model in nude mice. RESULTS: CYGB expression was downregulated in breast cancer tissues and cell lines, which was associated with promoter methylation. Ectopic CYGB expression suppressed proliferation, migration, invasion and induced apoptosis in breast cancer cell lines MCF7 (p53WT) and MB231 (p53mt) in vitro, and inhibited xenograft tumor growth in vivo. By proteomics and metabolomics analysis, glucose metabolism was found to be one of the main pathways suppressed by CYGB. The CYGB-expressing cells had lower ATP and compromised glycolysis. Additionally, CYGB suppressed key glucose metabolism factors including GLUT1 and HXK2 in p53-dependent and -independent manners. Restoration of GLUT1 or HXK2 expression attenuated CYGB-mediated proliferation suppression and apoptosis induction. CONCLUSIONS: CYGB is a potential tumor suppressor in breast cancer that is epigenetically suppressed. The results for the first time suggest that CYGB suppresses breast cancer through inhibiting glucose metabolism, which could be exploited for breast cancer prevention and therapy.