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Hypoxia is a critical feature of solid tumors and exerts crucial roles in cancers, including breast cancer. However, the detailed relationship between lncRNA-miRNA-mRNA triple network and hypoxia in breast cancer is still indistinct. In this study, a series of in silico analyses and online databases or tools were employed to establish a hypoxia-related lncRNA-miRNA-mRNA network in breast cancer based on competing endogenous RNA mechanism at single-cell resolution. RAMP2-AS1 was, eventually, identified as the most potential lncRNA, which was significantly negatively associated with hypoxia in breast cancer. Compared with normal controls, RAMP2-AS1 was markedly downregulated in breast cancer. Moreover, survival analysis revealed favorable prognostic values of RAMP2-AS1 in total or in specific clinicopathological breast cancer patients. Next, miR-660-5p, miR-2277-5p and miR-1301-3p, upregulated and possessed poor prognostic values in breast cancer, were identified as three potential downstream miRNAs of RAMP2-AS1. Then, the most potential downstream hypoxia-related genes (ATM and MYH11) of RAMP2-AS1/miRNA axis in breast cancer were screened out. Intriguingly, in vitro experiments confirmed that RAMP2-AS1 was a hypoxia-suppressed lncRNA and miR-660-5p/ATM was a potential downstream axis of RAMP2-AS1 in breast cancer. Collectively, our current data elucidated a key hypoxia-suppressed lncRNA RAMP2-AS1 and its possible miRNA-mRNA regulatory mechanism in breast cancer.
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Sorafenib resistance is a major obstacle influencing its therapeutic efficacy in advanced hepatocellular carcinoma (HCC). The knowledge of circular RNAs (circRNAs), a group of novel endogenous non-coding RNAs, in sorafenib resistance of HCC is still inadequate. In this study, a series of bioinformatic analyses and validation were performed. Firstly, a dataset GSE101850 was included for screening out differentially expressed circRNAs between sorafenib resistant and sensitive HCC, after which the structural patterns and binding microRNAs (miRNAs) of these candidate circRNAs were acquired. By combination of the results from expression, prognosis and diagnosis analysis, miR-221-3p and miR-222-3p were selected as the most potential binding miRNAs of hsa_circ_0006220, which was correlated with sorafenib resistance of HCC. Next, the target genes of miR-221-3p and miR-222-3p were predicted. Subsequently, ESR1 was identified as the top one hub gene among all these target genes. By conducting survival analysis and correlation analysis, ESR1 and KDR were considered as the most potential genes associated with sorafenib resistance of HCC. Collectively, we elucidated a potential hsa_circ_0006220-miR-221/222-3p-ESR1/KDR regulatory axis linked to sorafenib resistance of HCC.
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Liver metastasis is the main lethal cause of colorectal cancer (CRC). The knowledge of role and mechanism of circular RNA (circRNA) in liver metastasis of CRC is still inadequate. In this study, whole-transcriptome analysis was performed using three datasets (GSE147597, GSE147602 and GSE147603). A total of 14 potential circRNAs were identified, after which their structural patterns and binding miRNAs were obtained. Next, 45 differentially expressed miRNAs (DEmiRNAs) between CRC without and with liver metastasis were acquired, consisting 38 upregulated and 7 downregulated miRNAs. After conducting intersection analysis, expression validation and correlation analysis, miR-761 and miR-424-5p were selected as the most potential miRNAs linked to liver metastasis of CRC. Subsequently, the target genes of miR-761 or miR-424-5p were predicted and differentially expressed genes (DEGs) between CRC without and with liver metastasis were obtained. 257 genes that were commonly appeared in predicted genes and DEGs were significantly enriched in "epithelial-to-mesenchymal transition" and "signaling by Robo receptor". Among these enriched genes, only TPM2, SRPX and SRGAP1 were significantly negatively correlated with miR-424-5p and were positively linked to hsa_circ_0000375 in CRC without or with liver metastasis. Collectively, the current findings elucidated a potential hsa_circ_0000375-miR-424-5p-TPM2/SRPX/SRGAP1 network contributing to liver metastasis of CRC.
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Cuproptosis is a novel form of programmed cell death. The role and mechanism of cuproptosis-related genes in prostate adenocarcinoma have not been fully understood. In this study, a series of bioinformatic analyses were performed. Consequently, glycine cleavage system protein H with high expression and unfavorable prognosis was regarded as the most potential cuproptosis-related gene in prostate adenocarcinoma. Moreover, glycine cleavage system protein H might be a promising indicator for predicting leuprolide sensitivity in prostate adenocarcinoma and three potential drugs targeting glycine cleavage system protein H were identified. Enrichment analysis revealed that glycine cleavage system protein H-correlated genes were significantly enriched in tricarboxylic acid cycle-related pathways. Subsequently, small nucleolar RNA host gene 17/miR-29a-3p axis was found to partially account for overexpression of glycine cleavage system protein H in prostate adenocarcinoma. Collectively, the current study elucidated a potential cuproptosis-related competing endogenous RNA axis small nucleolar RNA host gene 17/miR-29a-3p/glycine cleavage system protein H in prostate adenocarcinoma.
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BACKGROUND: The interest in breast cancer with low HER2 expression as a distinct subtype is increasing. We aimed to explore the differences between HER2-low and HER2-zero breast cancer in their prognosis and rate of pathological complete response (pCR) after neoadjuvant therapy. METHODS: The National Cancer Database (NCDB) was used to select patients with breast cancer who received neoadjuvant therapy from 2004 to 2017. Logistic regression model was constructed for analysis of pCR. Cox proportional hazards regression model and Kaplan-Meier method were used for survival analysis. RESULTS: A total of 41500 breast cancer patients were included, among which 14814 (35.7%) had HER2-zero tumors and 26686 (64.3%) had HER2-low. HER2-low tumors were more commonly HR-positive in comparison with HER2-zero (66.3% versus 47.1%, P < 0.001). A lower rate of pCR was observed in HER2-low tumors than in HER2-zero tumors after neoadjuvant therapy in the total cohort (OR = 0.90; 95% CI [0.86-0.95]; P < 0.001) and in the subset of HR-positive (OR = 0.87; 95% CI [0.81-0.94]; P < 0.001). Patients with HER2-low tumors had a significantly superior survival than those with HER2-zero tumors (HR = 0.90; 95% CI [0.86-0.94]; P < 0.001), regardless of the HR status. Additionally, a marginal survival difference was also observed between HER2 IHC1+ and HER2 IHC2+/ISH-negative (HR = 0.91; 95% CI [0.85-0.97]; P = 0.003) cohorts. CONCLUSION: HER2-low tumors are a clinically relevant breast cancer subtype that is distinct from HER2-zero tumors. These findings may provide clues to appropriate therapeutic strategies for this subtype in the future.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Quimioterapia Adjuvante , Prognóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Metastasis is a leading cause to treatment failure in hepatocellular carcinoma (HCC) patients. Exosomes act as pivotal mediators in communication between different cells and exert effects on recipient cells by delivering bioactive cargoes, such as microRNAs (miRNAs). MiRNAs function in multiple steps of HCC development, including metastasis. MiR-374c-5p was previously identified as a tumor suppressor in some malignancies, while the current knowledge of its role in HCC metastasis is still limited. Herein, miR-374c-5p was found to be downregulated in HCC cell lines and clinical samples, and positively related with favorable prognosis in HCC patients. MiR-374c-5p transferred by exosomes derived from bone marrow mesenchymal stem cell (BMSC) suppressed migration, invasion and proliferation of HCC cells. LIMK1 was verified as downstream target gene of miR-374c-5p. Knockdown of LIMK1 reduced invasion, migration and proliferation of HCC cells, whereas overexpression functioned oppositely. The miR-374c-5p/LIMK1 axis suppressed epithelial-mesenchymal transition (EMT) by inactivating Wnt/ß-catenin pathway. In addition, miR-374c-5p was downregulated and LIMK1 upregulated in TGF-ß1 induced EMT. This EMT model could be reversed by LIMK1 silencing or miR-374c-5p overexpression. These results suggest that exo-miR-374c-5p suppresses EMT via targeting LIMK1-Wnt/ß-catenin axis and the axis is involved in TGF-ß1 induced metastasis of HCC, thereby identifying miR-374c-5p as a potential target for HCC treatment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Células-Tronco Mesenquimais , MicroRNAs , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Transição Epitelial-Mesenquimal/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Células-Tronco Mesenquimais/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , Proliferação de Células/genética , Quinases Lim/genética , Quinases Lim/metabolismoRESUMO
Pancreatic adenocarcinoma is one of the leading lethal human cancer types and is notorious for its poor prognosis. A series of bioinformatic analyses and experimental validations were employed to explore the role and mechanism of pseudogene-derived RNAs in pancreatic adenocarcinoma. Consequently, a total of 13 upregulated and 7 downregulated pseudogene-derived RNAs in pancreatic adenocarcinoma were identified. Survival analysis revealed a statistically predictive role of AK4P1 for unfavourable prognosis of patients with pancreatic adenocarcinoma. Subcellular location analysis indicated that AK4P1 was mainly located in cytoplasm, in which AK4P1 might competitively bind to tumour suppressive miR-375 in pancreatic adenocarcinoma. Further analysis showed that SP1 was a potential downstream target gene of miR-375 in pancreatic adenocarcinoma. Intriguingly, expression determination validated that SP1 could positively regulate AK4P1 levels in pancreatic adenocarcinoma. Finally, AK4P1 might also exert its effects by interacting with oncogenic parental gene AK4 in pancreatic adenocarcinoma. Conclusively, the present study elucidated a key regulatory loop AK4P1/miR-375/SP1 in pancreatic adenocarcinoma.
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Adenocarcinoma , MicroRNAs , Neoplasias Pancreáticas , Humanos , Adenocarcinoma/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Adenilato Quinase/metabolismo , Neoplasias PancreáticasRESUMO
Recent studies have well demonstrated that 5-methylcytosine (m5C) regulators play pivotal roles in pathological conditions, including cancer. This study first tried to identify potential 5-methylcytosine (m5C) regulators in breast cancer by combination of expression, diagnosis, and survival analyses, and then established an ncRNA-mRNA network accounting for m5C regulators' roles in breast cancer. Among 13 m5C regulators, DNMT3B and ALYREF were significantly upregulated in breast cancer and their high expression indicated unfavorable prognosis. Both DNMT3B and ALYREF possessed the statistical abilities to distinguish breast cancer from normal breast samples. Moreover, five potential upstream miRNAs (let-7b-5p, miR-195-5p, miR-29a-3p, miR-26a-5p, and miR-26b-5p) of m5C regulators could not only serve as independent prognostic predictors but also together made up a promising miRNA prognostic signature in breast cancer. Next, upstream potential lncRNAs of the five miRNAs were predicted and analyzed. Pathway enrichment analysis revealed that the target genes of these miRNAs were markedly enriched in some cancer-related pathways, and further investigation indicated VEGFA and EZH2 were found to be the most potential target genes in the m5C regulators-related ncRNA-mRNA network in breast cancer. These findings comprehensively provided key clues for developing m5C regulators-related effective therapeutic targets and promising diagnostic biomarkers in breast cancer.
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INTRODUCTION: Cancer is the leading cause of death among children. OBJECTIVES: We report on the latest estimates of the burden of cancer among children at the global, regional, and national levels from 1990 to 2019. METHODS: Based on the Global Burden of Disease Study 2019, children's cancer data were analyzed by sex, age, year, and location. Age-standardized rates were used to compare the burdens among regions and nations. Joinpoint analysis was applied to assess the temporal trend of the global childhood cancer burden. RESULTS: In 2019, 291,319 (95% uncertainty interval [UI], 254,239 to 331,993) new cases and 98,834 (86,124 to 113,581) deaths from childhood cancer were documented globally. Further, 8,302,464 (7,230,447 to 9,555,118) DALYs and 1,806,630 (1,567,808 to 2,089,668) prevalent cases were recorded in the same year. Age-standardized incidence and prevalence rates of childhood cancer were greatest in higher SDI settings and increased most significantly in Australasia and Southern Latin America over the last 30 years. However, although age-standardized death and DALY rates of childhood cancer have remarkably decreased in all regions since 1990, countries with a lower SDI showed the highest rates in 2019, particularly in countries in Eastern Sub-Saharan Africa. Among all cancers, leukemia has shown the largest decrease in burden since 1990. Despite this, leukemia was still the most common cancer and the leading cause of death among children in 2019, followed by brain and central nervous system cancer. CONCLUSIONS: On a global scale, the childhood cancer burden has significantly fallen over the last 30 years, but is still higher in lower SDI countries. Effective interventions and collaborations among nations should be facilitated to improve healthcare among children with cancer in countries with lower SDI.
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Neoplasias do Sistema Nervoso Central , Leucemia , Adulto , Criança , Carga Global da Doença , Saúde Global , Humanos , Leucemia/epidemiologia , Anos de Vida Ajustados por Qualidade de VidaRESUMO
Introduction: This study aimed to describe the latest epidemiology of female breast cancer globally, analyze the change pattern of the incidence rates and the disease's association with age, period, and birth cohort, and subsequently present a forecast of breast cancer incidence. Methods: Data for analysis were obtained from Global Burden of Disease (GBD) Study 2019 and World Population Prospects 2019 revision by the United Nations (UN). We described the age-standardized incidence rates (ASIRs) from 1990 to 2019 and then calculated the relative risks of period and cohort using an age-period-cohort model, and predicted the trends of ASIRs to 2035. Results: In 2019, the global incidence of breast cancer in women increased to 1,977,212 (95% uncertainty interval = 1 807 615 to 2 145 215), with an ASIR of 45.86 (41.91 to 49.76) per 100 000 person-year. Among the six selected countries facing burdensome ASIRs, only the USA showed a downward trend from 1990 to 2019, whereas the others showed an increasing or stable trend. The overall net drift was similar in Japan (1.78%), India (1.66%), and Russia (1.27%), reflecting increasing morbidity from 1990 to 2019. The increase in morbidity was particularly striking in China (2.60%) and not significant in Germany (0.42%). The ASIRs were predicted to continue to increase globally, from 45.26 in 2010 to 47.36 in 2035. In most countries and regions, the age specific incidence rate is the highest in those aged over 70 years and will increase in all age groups until 2035. In high-income regions, the age specific incidence rates are expected to decline in women aged over 50 years. Conclusions: The global burden of female breast cancer is becoming more serious, especially in developing countries. Raising awareness of the risk factors and prevention strategies for female breast cancer is necessary to reduce future burden.
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Background: Exposure to ambient particulate matter pollution (APMP) is a global health issue that directly affects the human respiratory system. Thus, we estimated the spatiotemporal trends in the burden of APMP-related respiratory diseases from 1990 to 2019. Methods: Based on the Global Burden of Disease Study 2019, data on the burden of APMP-related respiratory diseases were analyzed by age, sex, cause, and location. Joinpoint regression analysis was used to analyze the temporal trends in the burden of different respiratory diseases over the 30 years. Results: Globally, in 2019, APMP contributed the most to chronic obstructive pulmonary disease (COPD), with 695.1 thousand deaths and 15.4 million disability-adjusted life years (DALYs); however, the corresponding age-standardized death and DALY rates declined from 1990 to 2019. Similarly, although age-standardized death and DALY rates since 1990 decreased by 24% and 40%, respectively, lower respiratory infections (LRIs) still had the second highest number of deaths and DALYs attributable to APMP. This was followed by tracheal, bronchus, and lung (TBL) cancer, which showed increased age-standardized death and DALY rates during the past 30 years and reached 3.78 deaths per 100,000 persons and 84.22 DALYs per 100,000 persons in 2019. Among children aged < 5 years, LRIs had a huge burden attributable to APMP, whereas for older people, COPD was the leading cause of death and DALYs attributable to APMP. The APMP-related burdens of LRIs and COPD were relatively higher among countries with low and low-middle socio-demographic index (SDI), while countries with high-middle SDI showed the highest burden of TBL cancer attributable to APMP. Conclusions: APMP contributed substantially to the global burden of respiratory diseases, posing a significant threat to human health. Effective actions aimed at air pollution can potentially avoid an increase in the PM2.5-associated disease burden, especially in highly polluted areas.
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Poluição do Ar , Doenças Respiratórias , Adulto , Idoso , Poluição do Ar/efeitos adversos , Criança , Pré-Escolar , Carga Global da Doença , Humanos , Material Particulado/efeitos adversos , Anos de Vida Ajustados por Qualidade de Vida , Doenças Respiratórias/epidemiologiaRESUMO
Abstract: Background Growing evidences have showed that mucins (MUCs) are linked to occurrence and progression of human cancers. However, a comprehensive study regarding the expression, diagnosis, prognosis and mechanism of MUCs in breast cancer remains absent. Methods: A series of in silico analyses were employed in this study. Results: After performing comprehensive analysis for MUCs, MUC14 was identified as the most potential regulator in breast cancer, with downregulated expression in both mRNA and protein levels and significant diagnostic and prognostic values in breast cancer. Mechanistic exploration revealed that a potential ncRNA-mRNA axis, involving LINC01128/LINC01140/SGMS1-AS1/LINC00667-miR-137/miR-429-BCL2, might be partially responsible for MUC14's functions in breast cancer. Conclusions: Collectively, our study elucidated a key role of MUC14 in breast cancer and also provided some clues for explanation of the molecular action mechanism of MUC14 in breast cancer.
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Neoplasias da Mama/genética , Biologia Computacional/métodos , Regulação para Baixo , Sialoglicoproteínas/genética , Sialoglicoproteínas/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , MicroRNAs/genética , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Longo não Codificante/genética , Análise de SobrevidaRESUMO
Background: Epidemiological trends of type 2 diabetes mellitus attributable to fine particulate matter (PM2.5) pollution remain unclear. Here, we estimated spatiotemporal trends of type 2 diabetes mellitus burden attributable to PM2.5 pollution, including ambient particulate matter pollution (APMP) and household air pollution (HAP), from 1990-2019. Methods: Data were obtained from the Global Burden of Disease Study 2019 and were analyzed by age, sex, year, and location. Joinpoint regression analysis was applied in the analysis of temporal trends in type 2 diabetes mellitus burden over the 30 years. Results: Globally, PM2.5 pollution contributed to 292.5 thousand deaths and 13 million disability-adjusted life-years (DALYs) in 2019. APMP ranked third among all risk factors, causing an increase in type 2 diabetes mellitus burden from 1990, whereas the impact of HAP significantly fell during the same period. Both APMP and HAP contributed the most to deaths and DALYs of type 2 diabetes mellitus among older people. However, the age-standardized death and DALY rates of type 2 diabetes mellitus attributable to APMP were greater among males and people in the middle socio-demographic index countries, especially in Southern Sub-Saharan Africa. For HAP, type 2 diabetes mellitus burden was modestly higher in females and was highest in Oceania, which was the only region with an increase from 1990. Conclusions: PM2.5 pollution resulted in substantial and increasing type 2 diabetes mellitus burden worldwide. Hence, governments and health systems should take steps to reduce air pollution to mitigate this increasing burden.
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Poluição do Ar/efeitos adversos , Diabetes Mellitus Tipo 2/etiologia , Material Particulado/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Efeitos Psicossociais da Doença , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Carga Global da Doença , Saúde Global , Humanos , Expectativa de Vida , Masculino , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Adulto JovemRESUMO
Hepatocellular carcinoma (HCC) patients usually fail to be treated because of drug resistance, including sorafenib. In this study, the effects of CASK in HCC were investigated using gain- or loss-of-function strategies by performing cell counting kit-8 assay, colony formation assay, flow cytometry, transmission electron microscopy, immunofluorescent confocal laser microscopy, tumor xenograft experiment and immunohistochemistry staining. The current results suggested that CASK expression was positively associated with sorafenib resistance and poor prognosis of HCC. Moreover, inhibition of CASK increased the role of sorafenib partially by promoting apoptosis and autophagy, while CASK overexpression presented the opposite effects. Besides, when treatment with sorafenib, inhibition of apoptosis using the pan-caspase inhibitor Z-VAD-FMK and inhibition of autophagy using autophagy inhibitor 3-Methyladenine (3-MA) or small interfering RNA (siRNA) of LC3B all significantly reversed CASK knockout-induced effects, suggesting that both apoptosis and autophagy were involved in CASK-mediated above functions and autophagy played a pro-death role in this research. Intriguingly, similar results were observed in vivo. In molecular level, CASK knockout activated the c-Jun N-terminal kinase (JNK) pathway, and treatment with JNK inhibitor SP600125 or transiently transfected with siRNA targeting JNK significantly attenuated CASK knockout-mediated autophagic cell death. Collectively, all these results together indicated that CASK might be a promising biomarker and a potential therapeutic target for HCC patients.
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Hepatocellular carcinoma (HCC) is notorious for its poor prognosis. Increasing evidence has demonstrated that semaphorin 3F (SEMA3F) plays key roles in initiation and progression of several types of human cancer. However, the specific role and mechanism of SEMA3F in HCC remains not fully determined. In this study, we first performed pan-cancer analysis for SEMA3F's expression and prognosis using The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) data and found that SEMA3F might be a potential oncogene in HCC. Subsequently, noncoding RNAs (ncRNAs) contributing to SEMA3F overexpression were identified by a combination of a series of in silico analyses, including expression analysis, correlation analysis, and survival analysis. Finally, the TMPO-AS1/SNHG16-let-7c-5p axis was identified as the most potential upstream ncRNA-related pathway of SEMA3F in HCC. Moreover, SEMA3F level was significantly positively associated with tumor immune cell infiltration, biomarkers of immune cells, and immune checkpoint expression. Collectively, our findings elucidated that ncRNAs-mediated upregulation of SEMA3F correlated with poor prognosis and tumor immune infiltration in HCC.
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Pancreatic cancer, the most lethal malignant tumor, is notorious for its poor prognosis and metastatic potential. Non-coding RNAs (ncRNAs) are reported to play key roles in cancer metastasis. In this study, miRNA and gene expression profiles between metastatic pancreatic cancer cell M8 and its parental cell BxPC.3 were determined. Using differential expression analysis, survival analysis, target gene prediction, pathway enrichment analysis, intersection analysis and correlation analysis, hsa-miR-30d-5p/GJA1 axis was identified as the most potential pathway involved in metastasis of pancreatic cancer. Subsequently, two upstream lncRNAs (HELLPAR and OIP-AS1) and four upstream pseudogenes (AC093616.1, AC009951.1, TMEM183B and PABPC1P4) of hsa-miR-30d-5p/GJA1 axis were predicted and were then identified via assessment of RNA-RNA expression relationship. Furthermore, CTNNA1, CTNNB1 and CTNND1 were regarded as three crucial molecules to be participated in hsa-miR-30d-5p/GJA1-mediated metastatic potential in pancreatic cancer. In conclusion, we established a novel lncRNA/pseudogene-hsa-miR-30d-5p-GJA1 regulatory network linked to metastasis of pancreatic cancer.
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Conexina 43 , MicroRNAs , Neoplasias Pancreáticas , RNA Longo não Codificante , Conexina 43/genética , Conexina 43/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Pancreáticas/genética , Pseudogenes , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , TranscriptomaRESUMO
PURPOSE: The frequency in resistance to sorafenib accounts for the grim prognosis of advanced hepatocellular carcinoma (HCC). In the present study, we explore the anti-cancer efficacy of co-administration of sub-toxic AG-1024 with sorafenib in HCC cells to enhance the sensitivity of these cells to sorafenib. MATERIALS AND METHODS: Two acquired sorafenib-resistant HCC cells, SNU-sora-5 and SK-sora-5, were established and verified. The MTT assay, colony formation assay, cell morphology detection and flow cytometric analysis were then used to determine the anti-tumor effects of the co-administration of sub-toxic AG-1024 and sorafenib. Finally, the potential molecular mechanism was preliminarily examined. RESULTS: Compared to parental cell lines, the acquired sorafenib-resistant cell lines, SNU-sora-5 and SK-sora-5, were more resistant to sorafenib. Sub-toxic AG-1024 markedly enhanced sorafenib-mediated cell inhibition in acquired sorafenib-resistant HCC strains, with a reversal index (RI) of 4.64 in SNU-sora-5 and 4.58 in SK-sora-5 cell lines. Moreover, co-administration of sub-toxic AG-1024 and sorafenib exerted dramatic cytotoxicity compared with sorafenib alone in the intrinsic sorafenib-resistant HCC-LM3 cells. In contrast to high-dose sorafenib, sub-toxic AG-1024 combined with sorafenib had less impact on apoptosis while significantly enhancing G1/S arrest via activation of the mTOR/p21 signaling pathway. The more, pharmacological inhibition of mTOR activity by inhibitor Palomid 529 significantly antagonized the synergistic anti-cancer effects of AG-1024 and sorafenib in HCC cells. CONCLUSION: The current findings indicate that sub-toxic AG-1024 may be a promising therapeutic agent in enhancing the sensitivity in HCC cells to sorafenib, bringing hope to HCC patients refractory to sorafenib treatment.
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MicroRNAs (miRNAs) are frequently aberrantly expressed in hepatocellular carcinoma (HCC) and are involved in its development. However, their role and mechanism in HCC are still not fully elucidated. Differential expression analysis and survival analysis were performed to identify potential miRNAs in HCC and miR-3607 was identified as a candidate therapeutic target and prognostic biomarker. RT-qPCR confirmed the low expression of mature miR-3607-3p and miR-3607-5p in HCC. Functional experiments suggested that both miR-3607-3p and miR-3607-5p significantly inhibited HCC proliferation and induced apoptosis. Next, the detailed mechanism of miR-3607-3p and miR-3607-5p in HCC was explored by combination of bioinformatic analysis and experimental validation, and uncovered that XIAP, a common target gene of miR-3607-3p and miR-3607-5p, was involoved in their tumor suppressive effects. Finally, a XIAP-associated protein-protein interaction network, consisting of 10 positively correlated genes, was established. Collectively, we for the first time suggest that miR-3607-3p and miR-3607-5p inhibit HCC by acting one common target XIAP.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Apoptose , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismoRESUMO
The aim of this study was to establish a novel competing endogenous RNA (ceRNA) network able to predict prognosis in patients with triple-negative breast cancer (TNBC). Differential gene expression analysis was performed using the GEO2R tool. Enrichr and STRING were used to conduct protein-protein interaction and pathway enrichment analyses, respectively. Upstream lncRNAs and miRNAs were identified using miRNet and mirTarBase, respectively. Prognostic values, expression, and correlational relationships of mRNAs, lncRNAs, and miRNAs were examined using GEPIA, starBase, and Kaplan-Meier plotter. It total, 860 upregulated and 622 downregulated differentially expressed mRNAs were identified in TNBC. Ten overexpressed and two underexpressed hub genes were screened. Next, 10 key miRNAs upstream of these key hub genes were predicted, of which six upregulated miRNAs were significantly associated with poor prognosis and four downregulated miRNAs were associated with good prognosis in TNBC. NEAT1 and MAL2 were selected as key lncRNAs. An mRNA-miRNA-lncRNA network in TNBC was constructed. Thus, we successfully established a novel mRNA-miRNA-lncRNA regulatory network, each component of which is prognostic for TNBC.
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Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Transcriptoma/genética , Neoplasias de Mama Triplo Negativas/genética , Biomarcadores Tumorais/genética , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , MicroRNAs/genética , Prognóstico , RNA Longo não Codificante/genética , RNA Mensageiro/genéticaRESUMO
Recently, growing studies have demonstrated that circular RNAs (circRNAs) function as critical players in multiple human tumors, including papillary thyroid carcinoma (PTC). However, the expression and underlying potential mechanism of circRNAs in PTC are still not fully elucidated. In this study, 14 candidate differentially expressed circRNAs (DECs) between normal thyroid tissues and benign thyroid tissues or PTC were first screened using the GSE93522 dataset by the GEO2R online tool. Then, the structural loop graphs of these 14 circRNAs were obtained through the CSCD database. After performing miRNA co-prediction by combination of CSCD and CRI databases, a potential circRNA-miRNA sub-network, consisting of 9 circRNAs and 21 miRNAs, was successfully constructed. Subsequently, the expression and prognostic values of these miRNAs were further determined by starBase, and two miRNAs, namely, miR-605-5p and miR-876-3p, were identified as key miRNAs in PTC. Then, their downstream target genes were predicted by the miRNet database. CTNNB1 and CCND1 were found to be two most potential targets of miR-876-3p by combination of multiple in silico analyses, including protein-protein interaction (PPI), hub gene screening, correlation analysis, and expression analysis. Conclusively, we established a key hsa_circ_0088494-miR-876-3p-CTNNB1/CCND1 axis linked to carcinogenesis and progression of PTC, which may provide promising therapeutic targets in treating PTC in the future.