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In recent decades, using circulating tumor cell (CTC), circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), exosomes and etc. as liquid biomarkers has received enormous attention in various tumors, including breast cancer (BC). To date, efforts in the area of liquid biopsy predominantly focus on the analysis of blood-based markers. It is worth noting that the identifications of markers from non-blood sources provide unique advantages beyond the blood and these alternative sources may be of great significance in offering supplementary information in certain settings. Here, we outline the latest advances in the analysis of non-blood biomarkers, predominantly including urine, saliva, cerebrospinal fluid, pleural fluid, stool and etc. The unique advantages of such testings, their current limitations and the appropriate use of non-blood assays and blood assays in different settings are further discussed. Finally, we propose to highlight the challenges of these alternative assays from basic to clinical implementation and explore the areas where more investigations are warranted to elucidate its potential utility.
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Neoplasias da Mama , Células Neoplásicas Circulantes , Humanos , Feminino , Neoplasias da Mama/diagnóstico , Biomarcadores Tumorais/genética , Biópsia Líquida , DNA de Neoplasias/genética , RNA Neoplásico , Células Neoplásicas Circulantes/patologiaRESUMO
BACKGROUND: Circular RNAs (circRNAs) are a new class of endogenous non-coding RNAs (ncRNAs) widely expressed in eukaryotic cells. Mounting evidence has highlighted circRNAs as critical regulators of various tumours. More importantly, circRNAs have been revealed to recruit and reprogram key components involved in the tumour microenvironment (TME), and mediate various signaling pathways, thus affecting tumourigenesis, angiogenesis, immune response, and metastatic progression. In this review, we briefly introduce the biogenesis, characteristics and classification of circRNAs, and describe various mechanistic models of circRNAs. Further, we provide the first systematic overview of the interplay between circRNAs and cellular/non-cellular counterparts of the TME and highlight the potential of circRNAs as prospective biomarkers or targets in cancer clinics. Finally, we discuss the biological mechanisms through which the circRNAs drive development of resistance, revealing the mystery of circRNAs in drug resistance of tumours. SHORT CONCLUSION: Deep understanding the emerging role of circRNAs and their involvements in the TME may provide potential biomarkers and therapeutic targets for cancer patients. The combined targeting of circRNAs and co-activated components in the TME may achieve higher therapeutic efficiency and become a new mode of tumour therapy in the future.
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Biomarcadores Tumorais/genética , Neoplasias/patologia , RNA Circular/genética , Microambiente Tumoral/imunologia , Animais , Progressão da Doença , Humanos , Neoplasias/genética , Neoplasias/imunologia , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: Gastric cancer (GC) is the third leading cause of cancer-related mortality globally. Long noncoding RNAs (lncRNAs) are dysregulated in obvious malignancies including GC and exploring the regulatory mechanisms underlying their expression is an attractive research area. However, these molecular mechanisms require further clarification, especially upstream mechanisms. METHODS: LncRNA MNX1-AS1 expression in GC tissue samples was investigated via microarray analysis and further determined in a cohort of GC tissues via quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. Cell proliferation and flow cytometry assays were performed to confirm the roles of MNX1-AS1 in GC proliferation, cell cycle regulation, and apoptosis. The influence of MNX1-AS1 on GC cell migration and invasion was explored with Transwell assays. A xenograft tumour model was established to verify the effects of MNX1-AS1 on in vivo tumourigenesis. The TEAD4-involved upstream regulatory mechanism of MNX1-AS1 was explored through ChIP and luciferase reporter assays. The mechanistic model of MNX1-AS1 in regulating gene expression was further detected by subcellular fractionation, FISH, RIP, ChIP and luciferase reporter assays. RESULTS: It was found that MNX1-AS1 displayed obvious upregulation in GC tissue samples and cell lines, and ectopic expression of MNX1-AS1 predicted poor clinical outcomes for patients with GC. Overexpressed MNX1-AS1 expression promoted proliferation, migration and invasion of GC cells markedly, whereas decreased MNX1-AS1 expression elicited the opposite effects. Consistent with the in vitro results, MNX1-AS1 depletion effectively inhibited the growth of xenograft tumour in vivo. Mechanistically, TEAD4 directly bound the promoter region of MNX1-AS1 and stimulated the transcription of MNX1-AS1. Furthermore, MNX1-AS1 can sponge miR-6785-5p to upregulate the expression of BCL2 in GC cells. Meanwhile, MNX1-AS1 suppressed the transcription of BTG2 by recruiting polycomb repressive complex 2 to BTG2 promoter regions. CONCLUSIONS: Our findings demonstrate that MNX1-AS1 may be able to serve as a prognostic indicator in GC patients and that TEAD4-activatd MNX1-AS1 can promote GC progression through EZH2/BTG2 and miR-6785-5p/BCL2 axes, implicating it as a novel and potent target for the treatment of GC.
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Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Imediatamente Precoces/metabolismo , Proteínas Musculares/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Longo não Codificante/genética , Neoplasias Gástricas/patologia , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Proteínas de Ligação a DNA/genética , Progressão da Doença , Feminino , Proteínas de Homeodomínio/antagonistas & inibidores , Humanos , Proteínas Imediatamente Precoces/genética , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Proteínas Musculares/genética , Invasividade Neoplásica , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Antissenso/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Taxa de Sobrevida , Fatores de Transcrição de Domínio TEA , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND/AIMS: Lung cancer (LC) is a serious disease with high morbidity and mortality. Long noncoding RNAs (lncRNAs) have garnered attention because they participate in diverse human disorders, including cancer. Our study examined the long intergenic noncoding RNA 00707 (LINC00707). The effects of LINC00707 on lung adenocarcinoma (LAD) and molecular mechanisms are unclear. This study is aimed to investigate the role of LINC00707 in the malignant processes of LAD. METHODS: Quantitative reverse transcription PCR (qRT-PCR) was used to examine the expression level of LINC00707 in tissues and cell lines. The association of LINC00707 expression and postoperative prognosis was analyzed by the Kaplan-Meier method and log-rank test. Cell proliferation was evaluated in vitro and in vivo. Transwell assays were performed to examine cell migration. Cell cycle and apoptosis was determined by flow -cytometric and western blot analyses. Microarray analysis was conducted to screen for the downstream target gene Cdc42 of LINC00707, which was identified by qRT-PCR, functional analysis, and rescue experiment. RESULTS: The expression level of LINC00707 was clearly upregulated in LAD tissues compared to that in corresponding normal tissues. Its overexpression was related to advanced TNM stage, larger tumor size, lymphatic metastasis, and poor prognosis. Functional assays revealed that LINC00707 knockdown repressed LAD cell proliferation both in vitro and in vivo. This process may involve the inducing of G1 arrest and apoptosis. Moreover, cell migration was impaired after LINC00707 inhibition. Microarray analysis and rescue assays suggested that Cdc42 is an important target gene involved in the carcinogenesis of LINC00707. CONCLUSIONS: In summary, LINC00707 is a noncoding oncogene that exerts important regulatory functions in LAD, suggesting its potential as a biomarker in the prognosis and treatment of LAD.
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Adenocarcinoma/patologia , Neoplasias Pulmonares/patologia , RNA Longo não Codificante/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Células A549 , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma de Pulmão , Idoso , Animais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Humanos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , Regulação para Cima/genética , Proteína cdc42 de Ligação ao GTP/genéticaRESUMO
Long non-coding RNAs (lncRNAs) are fundamental agents that govern tumor growth and metastasis across a spectrum of cancer types. Linc01503 is a novel lncRNA situated on human chromosome 19, and it is intricately linked with the pathogenesis of multiple human cancers, underscoring its substantial role and significance in cancer development. It has been recognized as a pivotal contributor to inducing malignant behaviors in lung cancer, gastric cancer, colorectal cancer, cholangiocarcinoma, liver cancer and pancreatic cancer, among others. The dysregulation of linc01503 has been shown to strongly associate with advanced clinicopathological factors and foretell an unfavorable prognosis, indicating its prospective clinical significance as a valuable biomarker and therapeutic target for individuals with cancer. The primary objective of the current work is to present the intricate molecular pathways governed by linc01503 and its profound clinical relevance in the context of carcinogenesis. We also focus on the future prospects of linc01503-based clinical application. This will help us to better understand the regulatory mechanism of carcinogenesis and provide new ideas for precision molecular medicine.
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Neoplasias , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Neoplasias/genética , Neoplasias/terapia , Neoplasias/patologia , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismoRESUMO
The aberrant accumulation of intracellular disulfides in solute carrier family 7 member 11 (SLC7A11)high cells under glucose starvation induces disulfidptosis. Disulfidptosis has shown potential in tumor diagnosis and treatment.
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BACKGROUND: Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-positive (HER2+) breast cancer exhibits considerable heterogeneity, and it is of great interest whether patients with premenopausal HR+/HER2+ breast cancer treated with trastuzumab can benefit from ovarian function suppression (OFS) therapy similarly to HR+/HER2- breast cancer. Here, we conducted a real-world study in this population to identify both who would derive substantial benefits from the addition of OFS and clinicopathological factors with potential prognostic value. METHODS: Multicenter data from 253 premenopausal patients with HR+/HER2+ early-stage breast cancer who received trastuzumab from October 2009 to October 2018 were retrospectively included. The Kaplan-Meier method was used for survival analysis, while the log-rank test was used to compare the survival rates. Univariate and multifactor Cox regression analyses were performed to analyze the independent risk factors affecting invasive disease-free survival (IDFS). RESULTS: After a median follow-up of 98.50 months, compared with tamoxifen/toremifene alone, tamoxifen/toremifene/aromatase inhibitors plus OFS demonstrated significant benefits in the overall study population (HR = 0.289, 95% CI: 0.100-0.835, p = 0.022, 8-year IDFS rate: 90.78% vs. 95.54%), especially in the lymph node-positive subgroup and age ≤40 years subgroup. Age ≤40 years, histological grade >2, lymph node involvement, PR ≤50%, and tamoxifen alone were independent prognostic factors. CONCLUSIONS: For premenopausal HR+ breast cancer patients, HER2 positivity alone is an indication for the addition of OFS in adjuvant endocrine therapy. Age, histological grade, lymph node status, the expression of PR, and OFS treatment were independent prognostic factors in this population.
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Neoplasias da Mama , Humanos , Adulto , Feminino , Neoplasias da Mama/patologia , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Seguimentos , Prognóstico , Toremifeno/uso terapêutico , Estudos Retrospectivos , Tamoxifeno/uso terapêutico , Intervalo Livre de Doença , Quimioterapia AdjuvanteRESUMO
Background: HER2-low expression breast cancer (BC) accounts for approximately 45%-55% of all BC cases. The purpose of this study was to investigate the prognostic difference between patients with HER2-low expression and HER2-zero BC. Methods: An electronic search of Pubmed, Embase, Cochrane Library, and Web of Science databases was performed to screen studies that included prognostic comparisons between HER2-zero and HER2-low expression groups. A total of 14 studies involving 52106 patients were included. Results: Our results indicated that HER2-low expression was associated with a significant benefit in OS among all patients with early BC (HR, 0.83; 95% CI, 0.78-0.88), patients with hormone-receptor positive BC (HR, 0.83; 95% CI, 0.77-0.89), and patients with TNBC (HR, 0.78; 95% CI, 0.70-0.87). HER2-low expression was associated with a significant benefit in DFS among all patients (HR, 0.81; 95% CI, 0.71-0.93), patients with hormone receptor-positive BC (HR, 0.81; 95% CI, 0.72-0.90), but no significant difference in DFS was found in patients with TNBC (HR, 0.87; 95% CI, 0.65-1.17). HER2-low expression was associated with a significant benefit in RFS among all patients (HR, 0.90; 95% CI, 0.85-0.95), patients with hormone receptor-positive BC (HR, 0.90; 95% CI, 0.84-0.96), but no significant difference in RFS was found in patients with TNBC (HR, 0.80; 95% CI, 0.55-1.16). Conclusions: Among patients with early-stage BC, patients with HER2-low expression BC had better OS in the overall population, hormone receptor-positive and TNBC subgroups. Besides, favorable DFS and RFS were observed in both the overall population and hormone receptor-positive subgroup. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier (CRD 42022349458).
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N6-methyladenosine (m6A), the most prevalent RNA internal modification, is present in most eukaryotic species and prokaryotes. Studies have highlighted an intricate network architecture by which m6A epitranscriptome impacts on immune response and function. However, it was only until recently that the mechanisms underlying the involvement of m6A modification in immune system were uncovered. Here, we systematically review the m6A involvement in the regulation of innate and adaptive immune cells. Further, the interplay between m6A modification and anti-inflammatory, anti-viral and anti-tumour immunity is also comprehensively summarized. Finally, we focus on the future prospects of m6A modification in immune modulation. A better understanding of the crosstalk between m6A modification and immune system is of great significance to reveal new pathogenic pathways and to develop promising therapeutic targets of diseases.
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Adenosina , Metilação de DNA , Adenosina/metabolismo , Sistema Imunitário/metabolismo , LógicaRESUMO
BACKGROUND: To explore the relationship between L3 skeletal muscle index (SMI) and the prognosis of patients with stage IV gastric cancer (GC). METHODS: A total of 27 patients with stage IV GC requiring chemotherapy admitted to our hospital from 1 April 2015 to 20 May 2019 were selected as participants. The Kaplan-Meier method was used to describe the survival time of all participants. By evaluating the L3 plane CT images, the mass index (cm2/m2) of L3 skeletal muscle (including psoas major, erector spinae, quadratus psoas, transversus abdominis, external oblique abdominis, and internal oblique abdominis) was calculated to study the changes of L3 SMI during treatment and the correlation between L3 SMI and clinical features. The log-rank method was used to analyze the correlativity between the survival time of patients and their general data, L3 SMI, or other indicators. RESULTS: The survival time of 27 patients with stage IV GC was 7.4-49.9 months, with a mean survival time of 19.72 months and a median survival time of 16.17 months. The 1-year survival rate was 77.78%, and the 3-year survival rate was 7.41%. During treatment, L3 SMI continued to decline in 20 of the 27 participants (74.07%). After the first chemotherapy, 17 participants (62.96%) met the criteria of sarcopenia syndrome, and after the fourth chemotherapy, 19 participants (70.37%) met the criteria of sarcopenia syndrome. The L3 SMI was shown to be significantly correlated with body mass index (BMI) and Onodera's prognostic nutritional index (OPNI) (both P<0.05), but not with age, gender, dietary intake, and primary site (all P>0.05). Log-rank test showed that there was a correlation between L3 SMI and survival time of patients (P<0.05). The average survival time of participants with sarcopenia syndrome (16.78 months) was significantly lower than that of those without sarcopenia syndrome (25.58 months) (P<0.05). CONCLUSIONS: There is a significant correlation between L3 SMI and survival time, and L3 SMI can be used as a potential index to evaluate the prognosis of patients with stage IV GC.
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OBJECTIVES: Long non-coding RNAs (lncRNAs) are key mediators in various malignancies. Linc01503 was previously elucidated to promote gastric cancer (GC) cell invasion. However, the upstream mechanism of linc01503 and its involvement in GC cell cycle, apoptosis and tumorigenesis still remain unclear. MATERIALS AND METHODS: Bioinformatics analysis and quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays were implicated to detect linc01503 level in GC. The role of linc01503 was detected by in vitro functional assays and in vivo xenograft tumour models. The association between linc01503 and its upstream effector was identified by chromatin immunoprecipitation (ChIP) assays. The mechanistic model of linc01503 was clarified using subcellular separation, fluorescence in situ hybridization, RNA-sequencing, RNA immunoprecipitation (RIP) and ChIP assays. RESULTS: Linc01503 was remarkably elevated in GC and tightly linked with the overall survival of patients with GC. The key transcription factor early growth response protein 1 (EGR1) critically activated the transcription of linc01503. Functionally, linc01503 knockdown resulted in the activation of apoptosis and G1/G0 phase arrest in GC. Mechanistically, linc01503 interacted with histone modification enzyme enhancer of zeste 2 (EZH2) and lysine (K)-specific demethylase 1A (LSD1), thereby mediating the transcriptional silencing of dual-specificity phosphatase 5 (DUSP5) and cyclin-dependent kinase inhibitor 1A (CDKN1A) in GC. CONCLUSIONS: EGR1-activated linc01503 could epigenetically silence DUSP5/CDKN1A expression to mediate cell cycle progression and tumorigenesis, implicating it as a prospective target for GC therapeutics.
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Carcinogênese , Ciclo Celular , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , RNA Longo não Codificante/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Linhagem Celular Tumoral , Proteína 1 de Resposta de Crescimento Precoce/genética , Humanos , Camundongos , Camundongos Nus , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , RNA Longo não Codificante/genética , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: Tumor mutation burden (TMB) assessed by tumor-related gene panels (CRGP), microsatellite instability (MSI), and mismatch repair (MMR) has been proven to be associated with prognosis, and these factors are prognostic indicators in predicting the benefits of immune checkpoint blockade (ICB) in solid tumors. However, whether the TMB calculated by CRGPs, MSI, and MMR is associated with overall survival (OS) in patients with colorectal cancer (CRC) remains to be explored. METHODS: The prognostic threshold of the panel-TMB was explored by a panel of 645 genes (GP645) from 41 CRC patients in Jiangsu Cancer Hospital (JCH dataset). The results were further validated using 531 CRC patients from The Cancer Genome Atlas (TCGA) database. RESULTS: Mutations of the GP645 genes were distributed on 21 chromosomes. Spearman correlation analysis showed that the panel-TMB was positively correlated with TMB measured by whole-exome sequencing (WES) (wTMB) in the TCGA dataset (R=0.75, P<0.001). Kaplan-Meier survival analysis demonstrated that higher panel-TMB in CRC patients was significantly associated with a poor OS (P=0.0062). MSI and MMR status were determined using the GP645 by next-generation sequencing (NGS). The proportions of MSI-H and dMMR accounted for less than 10% in CRC, the vast majority of MSI-H/dMMR samples also had high TMB [positive predictive value (PPV) =66.6%], and only 13.3% of samples with high TMB were classified as MSI-high/dMMR. In addition, patients with low-TMB were associated with MSS/pMMR (96.2%), and these results are consistent with earlier studies. CONCLUSIONS: GP645 was constructed to evaluate OS in Chinese CRC patients. Panel-TMB and MSI/MMR might be potential prognostic predictors of CRC patients using the GP645.
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OBJECTIVE: To investigate the correlation between estrogen-related receptor a (ERRα) expression level and gastric cancer (GC). METHODS: We collected GC and adjacent normal tissues from 50 patients. The parameters of the patients were summarized, and correlation with the expression level of ERRα was calculated. Downregulated ERRα using lentivirus was designed and transfected to SGC-7901 and MGC-803 cells. Cell migration, invasion and wound assays were conducted to determine the correlation between ERRα and capacity for cell migration and invasion. The expression level of the genes involved in epithelial-mesenchymal transition, including E-cadherin, γ-catenin, N-cadherin and vimentin, was determined via real-time or quantitative polymerase chain reaction(qPCR) and Western blot analysis. RESULTS: The expression of ERRα tends to be higher in GC tissues than in adjacent normal tissues. Analyses ofthe expression level of ERRα and patient parameters show that the ERRα level is significantly correlated with TNM staging and patient survival (P<0.05). The downregulation of ERRα can inhibit cell invasion and migration, which was proven by Transwell and cell wound assays. The levels of E-cadherin and γ-catenin increased by conducting qPCR and Western blot analysis. Meanwhile, the levels of N-cadherin and vimentin decreased when ERRα expression was reduced. CONCLUSION: ERRα is highly expressed in GC tissues and can promote the migration and invasion of cancer cells. It can be a potential marker for GC diagnosis.
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Receptores de Estrogênio/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
OBJECTIVES: Long non-coding RNAs (lncRNAs) represent an important group of non-coding RNAs (ncRNAs) with more than 200 nucleotides in length that are transcribed from the so-called genomic "dark matter." Mounting evidence has shown that lncRNAs have manifested a paramount function in the pathophysiology of human diseases, especially in the pathogenesis and progression of cancers. Despite the exponential growth in lncRNA publications, our understanding of regulatory mechanism of lncRNAs is still limited, and a lot of controversies remain in the current lncRNA knowledge.The purpose of this article is to explore the clinical significance and molecular mechanism of SNHG15 in tumors. MATERIALS & METHODS: We have systematically searched the Pubmed, Web of Science, Embase and Cochrane databases. We provide an overview of current evidence concerning the functional role, mechanistic models and clinical utilities of SNHG15 in human cancers in this review. RESULTS: Small nucleolar RNA host gene 15 (SNHG15), a novel lncRNA, is identified as a key regulator in tumorigenesis and progression of various human cancers, including colorectal cancer (CRC), gastric cancer (GC), pancreatic cancer (PC) and hepatocellular carcinoma (HCC). Dysregulation of SNHG15 has been revealed to be dramatically correlated with advanced clinicopathological factors and predicts poor prognosis, suggesting its potential clinical value as a promising biomarker and therapeutic target for cancer patients. CONCLUSIONS: LncRNA SNHG15 may serve as a prospective and novel biomarker for molecular diagnosis and therapeutics in patients with cancer.
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Biomarcadores Tumorais/metabolismo , Carcinogênese/metabolismo , Neoplasias/metabolismo , RNA Longo não Codificante/metabolismo , RNA Neoplásico/metabolismo , Humanos , Neoplasias/diagnóstico , Neoplasias/terapiaRESUMO
Long non-coding RNAs (lncRNAs) are characterized as key layers of the genome in various cancers. TSPEAR-AS2 was highlighted to be a candidate lncRNA potentially involved in gastric cancer (GC) progression. However, the clinical significance and mechanism of TSPEAR-AS2 in GC required clarification. The clinical significance of TSPEAR-AS2 was elucidated through Kaplan-Meier Plotter. The mechanism of TSPEAR-AS2 in GC was clarified in vitro and in vivo using luciferase reporter, chromatin immunoprecipitation, RNA immunoprecipitation assays, and animal models. TSPEAR-AS2 elevation was closely correlated with overall survival of GC patients. A basic transcription element-binding protein 2 (BTEB2)-activated TSPEAR-AS2 model was first explored in this study. TSPEAR-AS2 silencing substantially reduced tumorigenic capacities of GC cells, while TSPEAR-AS2 elevation had the opposite effect. Mechanistically, TSPEAR-AS2 bound with both polycomb repressive complex 2 (PRC2) and argonaute 2 (Ago2). TSPEAR-AS2 knockdown significantly decreased H3K27me3 levels at promoter regions of gap junction protein alpha 1 (GJA1). Ago2 was recruited by TSPEAR-AS2, which was defined to sponge miR-1207-5p, contributing to the repression of claudin 4 (CLDN4) translation. The axis of EZH2/GJA1 and miR-1207-5p/CLDN4 mediated by BTEB2-activated-TSPEAR-AS2 plays an important role in GC progression, suggesting a new therapeutic direction in GC treatment.
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It was found in this study that long intergenic non-protein coding RNA 346 (LINC00346) was an lncRNA aberrantly expressed in gastric cancer (GC) based on multiple Gene Expression Omnibus (GEO) databases of GC cohorts. The LINC00346 gene was recurrently amplified and upregulated in GC, and its expression was positively correlated with poor pathologic stage, large tumor size, and poor prognosis. In addition, the oncogenic transcription factors KLF5 and MYC could bind to the LINC00346 promoter and enhance its expression. Gene Set Enrichment Analysis (GSEA) in the GEO datasets revealed that cell cycle and focal adhesion genes were enriched in patients with high LINC00346 expression. In vitro and in vivo assays of LINC00346 alterations revealed a complex integrated phenotype affecting cell growth, migration and invasion. Strikingly, high-throughput sequencing analysis after LINC00346 alterations highlighted alterations in cell cycle and focal adhesion pathways in GC cells. Mechanistically, argonaute 2 (Ago2) was recruited by LINC00346, which functioned as a molecular sponge for miR-34a-5p by antagonizing its ability to repress CD44, NOTCH1, and AXL protein translation. Taken together, our findings support a model in which the KLF5, MYC/LINC00346/miR-34a-5p cross-talk served as critical effectors in GC tumorigenesis and progression, suggesting a new therapeutic direction in the treatment of GC.
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Transformação Celular Neoplásica/genética , Fatores de Transcrição Kruppel-Like/genética , Proteínas Proto-Oncogênicas c-myc/genética , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Proteínas Argonautas/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Receptores de Hialuronatos/antagonistas & inibidores , MicroRNAs/genética , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptor Notch1/antagonistas & inibidores , Neoplasias Gástricas/patologia , Receptor Tirosina Quinase AxlRESUMO
Accumulating data indicate that long noncoding RNAs (lncRNAs) serve as important modulators in biological processes and are dysregulated in diverse tumors. The function of FOXD2-AS1 in gastric cancer (GC) progression and related biological mechanisms remain undefined. A comprehensive analysis identified that FOXD2-AS1 enrichment was upregulated markedly in GC and positively correlated with a large tumor size, a later pathologic stage, and a poor prognosis. Gene-set enrichment analysis (GSEA) in GEO datasets uncovered that cell cycle and DNA replication associated genes were enriched in patients with high FOXD2-AS1 expression. Loss of FOXD2-AS1 function inhibited cell growth via inhibiting the cell cycle in GC, whereas upregulation of FOXD2-AS1 expression promoted cancer progression. The enhancer of zeste homolog 2 (EZH2) and lysine (K)-specific demethylase 1A (LSD1) proteins were found to serve as binding partners of FOXD2-AS1 and mediators of FOXD2-AS1 function. Mechanically, FOXD2-AS1 promoted GC tumorigenesis partly through EZH2 and LSD1 mediated EphB3 downregulation. The present results revealed that FOXD2-AS1 acted as a tumor inducer in GC partly through EphB3 inhibition by direct interaction with EZH2 and LSD1, and may prove to be a potential biomarker of carcinogenesis.
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Carcinogênese/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Histona Desmetilases/genética , RNA Longo não Codificante/genética , Receptor EphB3/genética , Neoplasias Gástricas/genética , Regulação para Cima/genética , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Regulação para Baixo/genética , Epigênese Genética/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Transdução de Sinais/genética , Neoplasias Gástricas/patologiaRESUMO
OBJECTIVE To explore the effects of pterostilbene (PTE) on wound healing in diabetic skin ulcer model rats and its mechanism. METHODS Ten SD rats were grouped into control group; after diabetic skin ulcer model of other rats was induced by giving high-fat and high-sugar diet+intraperitoneal injection of streptozotocin+cutting off the skin and subcutaneous tissue in the marked area of the back, model rats were randomly divided into model group, PTE low-dose group (40 mg/kg), PTE high-dose group (80 mg/kg), PTE high-dose+PP2 group (80 mg/kg PTE+2 mg/kg SRC inhibitor PP2), with 10 rats in each group. On the second day after modeling, the rats in each drug group were intraperitoneally injected with corresponding drug solutions, while the rats in control group and model group were intraperitoneally injected with normal saline, once a day, for 14 consecutive days. The wound healing rate of rats in each group was measured on the 7th and 14th day of administration; the contents of interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF) in the serum of rats were detected; the pathological changes of wound granulation tissue were observed, and the expressions of SRC/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway-related proteins in wound granulation tissue were detected. RESULTS Compared with control group, the wound healing rate, serum content of VEGF, the phosphorylation levels of SRC, MEK1/2 and ERK1/2 were decreased significantly (P<0.05), while serum contents of IL- 1β, IL-6 and TNF-α were increased significantly (P<0.05); there was obvious infiltration of inflammatory cells in the wound granulation tissue, and the number of new blood vessels decreased. Compared with model group, above indexes of PTE low-dose and high-dose groups were improved significantly (P<0.05), and the pathological injury of granulation tissue in wound was improved. PP2 significantly reversed the improvement effects of PTE on the above indexes (P<0.05). CONCLUSIONS PTE can promote the wound healing of diabetic skin ulcer model rats, the mechanism of which may be related to activating SRC/MEK/ERK signaling pathway.