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2.
Surg Open Sci ; 12: 35-42, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36936452

RESUMO

Introduction: The effects of isoform-specific histone deacetylase inhibitors (HDACIs) and the non-selective HDACI on sepsis have been profoundly reported. However, the best HDAC classes have not been fully evaluated. Therefore, this study aimed to determine which HDACIs are responsible for survival and beneficial for organ injury. Methods: Experiment I, SD rats were subjected to cecal ligation and puncture and randomly assigned to the no treatment, dimethyl sulfoxide (DMSO) only, MS-275, LMK-235, tubastatinA (TubA), trichostatin-A (TSA), and sirtinol groups (n = 5). Survival was monitored for 48 h. Experiment II, the animals were monitored for 12 h, then, blood and tissues sample were collected. Interleukin (IL)-6, IL-1ß, tumour necrosis factor (TNF)-α, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK) and lactate dehydrogenase (LDH) expressions were evaluated using ELISA. Liver, heart and lung tissues were analysed via hematoxylin and eosin staining. Liver and heart tissue lysates were analysed for acetylated histones H3, H4, a-tubulin and nuclear factor kappa B (NF-κB), IL-6, IL-1ß, and TNF-α using western blotting. Splenocytes were examined via flow cytometry to analyse the immune cell population. Results: MS-275, TubA and TSA treatments significantly prolonged survival. MS-275, LMK-235, TubA and TSA significantly reduced the histopathological scores and AST, ALT, CK, LDH, IL-6, IL-1ß and TNF-α levels, significantly increased acetylated of NF-κB and changed the immune cell proportion. Conclusion: Our results indicated that HDACI classes I and IIb and non-selective HDACI can significantly prolong survival. Moreover, non-selective and isoform-specific class I and IIa/IIb HDACIs can attenuate inflammation and organ injury.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34659430

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is often diagnosed at a late stage, when the prognosis is poor. The regulation of long noncoding RNAs (lncRNAs) plays a crucial role in HCC. However, the precise regulatory mechanisms of lncRNA signaling in HCC remain largely unknown. Our study aims to investigate the underlying mechanisms of lncRNA (upregulated in hepatocellular carcinoma) URHC in HCC. OBJECTIVE: To study the in vivo and in vitro localization and biological effects of URHC on liver cancer cells. Through bioinformatics analysis, dual-luciferase reporter gene analysis and rescue experiments revealed the possible mechanism of URHC. METHODS: RT-qPCR, fluorescence in situ hybridization (FISH) staining, EdU, colony formation, and tumor xenograft experiments were used to identify localized and biological effects of URHC on HCC cells in vitro and in vivo. The bioinformatics analysis, dual-luciferase reporter assay, and rescue experiments revealed the potential mechanism of URHC. RESULTS: URHC silencing may inhibit the HCC cells' proliferation in vitro and in vivo. We found that URHC was mainly localized in the cytoplasm. The expression of miR-5007-3p was negatively regulated by URHC. And miR-5007-3p could reverse the effect of URHC in HCC cells. The expression of DNAJB9 was negatively regulated by miR-5007-3p but positively regulated by URHC. These suggestive of lncRNA-URHC positively regulated the level of DNAJB9 by sponging miR-5007-3p. CONCLUSION: Together, our study elucidated the role of URHC as a miRNA sponge in HCC and shed new light on lncRNA-directed diagnostics and therapeutics in HCC.

5.
Cancer Gene Ther ; 28(3-4): 221-233, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32801328

RESUMO

Long noncoding RNAs (lncRNAs) represent an emerging field of tumor biology, playing essential roles in cancer cell proliferation, invasion, and metastasis. However, the overall functional and clinical significance of most lncRNAs in pancreatic cancer is not thoroughly understood. Here, we described most of the lncRNAs with aberrant expression patterns in pancreatic cancer as detected by microarray. Quantitative real-time polymerase chain reaction further verified that the expression of LINC00671 was decreased in pancreatic cancer cell lines and patient samples. Furthermore, lower LINC00671 expression was associated with reduced tumor differentiation, aggressiveness, and poor prognosis. Functionally, LINC00671 overexpression inhibited pancreatic cancer cell proliferation, invasion, and migration in vitro, and reduced tumor growth in vivo. LINC00671 is mainly located in the cytoplasm. RNA sequencing and bioinformatics analyses indicated that LINC00671 binds to multiple miRNAs and therefore could be involved in multiple tumor-associated pathways, such as the AMPK signaling pathway and PI3K-Akt signaling pathway. Western blotting and immunohistochemistry further confirmed that LINC00671 overexpression suppressed the AKT, ERK, and epithelial-mesenchymal transition pathways. Overall, these results indicated that LINC00671 acts as a novel tumor suppressor in pancreatic cancer. Our findings may provide a new potential target for the treatment of pancreatic cancer.


Assuntos
Sistema de Sinalização das MAP Quinases , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Proliferação de Células/fisiologia , Feminino , Humanos , Camundongos , Metástase Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , RNA Longo não Codificante/genética , Análise de Sobrevida , Transfecção
6.
JCI Insight ; 5(20)2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33055424

RESUMO

Peptidylarginine deiminases (PADs) are a family of calcium-dependent enzymes that are involved in a variety of human disorders, including cancer and autoimmune diseases. Although targeting PAD4 has shown no benefit in sepsis, the role of PAD2 remains unknown. Here, we report that PAD2 is engaged in sepsis and sepsis-induced acute lung injury in both human patients and mice. Pad2-/- or selective inhibition of PAD2 by a small molecule inhibitor increased survival and improved overall outcomes in mouse models of sepsis. Pad2 deficiency decreased neutrophil extracellular trap (NET) formation. Importantly, Pad2 deficiency inhibited Caspase-11-dependent pyroptosis in vivo and in vitro. Suppression of PAD2 expression reduced inflammation and increased macrophage bactericidal activity. In contrast to Pad2-/-, Pad4 deficiency enhanced activation of Caspase-11-dependent pyroptosis in BM-derived macrophages and displayed no survival improvement in a mouse sepsis model. Collectively, our findings highlight the potential of PAD2 as an indicative marker and therapeutic target for sepsis.


Assuntos
Lesão Pulmonar Aguda/genética , Doenças Autoimunes/genética , Inflamação/genética , Proteína-Arginina Desiminase do Tipo 2/genética , Sepse/genética , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , Animais , Doenças Autoimunes/sangue , Doenças Autoimunes/patologia , Biomarcadores/sangue , Caspases Iniciadoras/genética , Armadilhas Extracelulares/genética , Regulação da Expressão Gênica/genética , Humanos , Inflamação/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Proteína-Arginina Desiminase do Tipo 2/antagonistas & inibidores , Piroptose/genética , Sepse/sangue , Sepse/complicações , Sepse/patologia
7.
Mol Oncol ; 14(6): 1381-1396, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32174012

RESUMO

Hepatocellular carcinoma (HCC) is one of the most lethal malignant diseases worldwide. Despite advances in the diagnosis and treatment of HCC, its overall prognosis remains poor. Recent studies have shown that long noncoding RNAs (lncRNAs) play crucial roles in various pathophysiological processes, including liver cancer. In the current study, we report that lncRNA SLC2A1-AS1 is frequently downregulated in HCC samples, as shown by quantitative real-time polymerase chain reaction analysis. SLC2A1-AS1 deletion is significantly associated with recurrence-free survival in HCC. By performing glucose uptake, lactate production and ATP detection assays, we found that SLC2A1-AS1-mediated glucose transporter 1 (GLUT1) downregulation significantly suppressed glycolysis of HCC. In vitro Cell Counting Kit-8, colony formation, transwell assays as well as in vivo tumorigenesis and metastasis assays showed that SLC2A1-AS1 overexpression significantly suppressed proliferation and metastasis in HCC through the transcriptional inhibition of GLUT1. Results from fluorescence in situ hybridization, ChIP and luciferase reporter assays demonstrated that SLC2A1-AS1 exerts its regulatory role on GLUT1 by competitively binding to transketolase and signal transducer and activator of transcription 3 (STAT3) and inhibits the transactivation of Forkhead box M1 (FOXM1) via STAT3, thus resulting in inactivation of the FOXM1/GLUT1 axis in HCC cells. Our findings will be helpful for understanding the function and mechanism of lncRNA in HCC. These data also highlight the crucial role of SLC2A1-AS1 in HCC aerobic glycolysis and progression and pave the way for further research regarding the potential of SLC2A1-AS1 as a valuable predictive biomarker for HCC recurrence.


Assuntos
Carcinoma Hepatocelular/genética , Progressão da Doença , Proteína Forkhead Box M1/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Glicólise/genética , Neoplasias Hepáticas/genética , RNA Longo não Codificante/metabolismo , Fator de Transcrição STAT3/metabolismo , Aerobiose , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Ligação Proteica , RNA Longo não Codificante/genética , Transdução de Sinais , Ativação Transcricional/genética
8.
Onco Targets Ther ; 13: 51-60, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021254

RESUMO

BACKGROUND: Coiled-coil domain-containing protein 34 (CCDC34), which belongs to the CCDCs family, has been recently reported to be up-regulated in various kinds of tumors. However, its role in the development of hepatocellular carcinoma (HCC) still remains unclear. MATERIALS AND METHODS: In this study, real-time polymerase chain reaction (RT-PCR) and Western blot analysis were performed to measure the mRNA and protein levels of CCDC34 in clinical samples. Kaplan-Meier method was used to analyze the relationship between CCDC34 and the prognosis in HCC patients. CCK-8 and colony formation assays were conducted to investigate CCDC34's effect on the cell proliferation, and Transwell assays were used to detect CCDC34's effect on the cell metastasis. Moreover, subcutaneous xenograft tumor model and lung metastasis model were applied to confirm the impact of CCDC34 on the HCC development. Lastly, RNA sequencing and Western blot analysis were performed to probe the underlying mechanism of CCDC34's effect on HCC. RESULTS: CCDC34 was significantly induced in HCC tissues, and the overexpression of CCDC34 predicted the poor outcomes among HCC patients. It was verified by the in vitro and in vivo experiments that CCDC34-knockdown potently inhibited the proliferation and metastasis of HCC cells. Subsequent results indicated that CCDC34 inhibition can affect the activation of protein kinase B (PKB or AKT) as well as epithelial-mesenchymal transition (EMT) process. CONCLUSION: CCDC34 is significantly associated with HCC. It will become a promising prognostic biomarker and therapeutic target against HCC.

9.
J Immunother Cancer ; 8(1)2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31940590

RESUMO

BACKGROUND: Developing the ability to use tumor-directed therapies to trigger potentially therapeutic immune responses against cancer antigens remains a high priority for cancer immunotherapy. We hypothesized that histotripsy, a novel non-invasive, non-thermal ablation modality that uses ultrasound-generated acoustic cavitation to disrupt tissues, could engender adaptive immune responses to tumor antigens. METHODS: Immunocompetent C57BL/6 mice inoculated with flank melanoma or hepatocellular carcinoma tumors were treated with histotripsy, thermal ablation, radiation therapy, or cytotoxic T lymphocyte-associated protein-4 (CTLA-4) blockade checkpoint inhibition. Lymphocyte responses were measured using flow cytometric and immunohistochemical analyses. The impact of histotripsy on abscopal immune responses was assessed in mice bearing bilateral tumors, or unilateral tumors with pulmonary tumors established via tail vein injection. RESULTS: Histotripsy ablation of subcutaneous murine melanoma tumors stimulated potent local intratumoral infiltration of innate and adaptive immune cell populations. The magnitude of this immunostimulation was stronger than that seen with tumor irradiation or thermal ablation. Histotripsy also promoted abscopal immune responses at untreated tumor sites and inhibited growth of pulmonary metastases. Histotripsy was capable of releasing tumor antigens with retained immunogenicity, and this immunostimulatory effect was associated with calreticulin translocation to the cellular membrane and local and systemic release of high mobility group box protein 1. Histotripsy ablation potentiated the efficacy of checkpoint inhibition immunotherapy in murine models of melanoma and hepatocellular carcinoma. CONCLUSIONS: These preclinical observations suggest that non-invasive histotripsy ablation can be used to stimulate tumor-specific immune responses capable of magnifying the impact of checkpoint inhibition immunotherapy.


Assuntos
Técnicas de Ablação/métodos , Antineoplásicos Imunológicos/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Ablação por Ultrassom Focalizado de Alta Intensidade/métodos , Neoplasias Hepáticas Experimentais/terapia , Melanoma Experimental/terapia , Animais , Terapia Combinada , Neoplasias Hepáticas Experimentais/imunologia , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL
10.
Xenotransplantation ; 26(3): e12497, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30767272

RESUMO

Pig liver xenotransplantation appears to be more perplexing when compared to heart or kidney xenotransplantation, even though great progress has been achieved. The relevant molecular mechanisms involved in xenogeneic rejection, including coagulopathy, and particularly thrombocytopenia, are complex, and need to be systematically investigated. The deletion of expression of Gal antigens in the liver graft highlights the injurious impact of nonGal antigens, which continue to induce humoral rejection. Innate immunity, particularly mediated by macrophages and natural killer cells, interplays with inflammation and coagulation disorders. Kupffer cells and liver sinusoidal endothelial cells (LSECs) together mediate leukocyte, erythrocyte, and platelet sequestration and phagocytosis, which can be exacerbated by increased cytokine production, cell desialylation, and interspecies incompatibilities. The coagulation cascade is activated by release of tissue factor which can be dependent or independent of the xenoreactive immune response. Depletion of endothelial anticoagulants and anti-platelet capacity amplify coagulation activation, and interspecies incompatibilities of coagulation-regulatory proteins facilitate dysregulation. LSECs involved in platelet phagocytosis and transcytosis, coupled with hepatocyte-mediated degradation, are responsible for thrombocytopenia. Adaptive immunity could also be problematic in long-term liver graft survival. Currently, relevant evidence and study results of various genetic modifications to the pig donor need to be fully determined, with the aim of identifying the ideal transgene combination for pig liver xenotransplantation. We believe that clinical trials of pig liver xenotransplantation should initially be considered as a bridge to allotransplantation.


Assuntos
Rejeição de Enxerto/imunologia , Xenoenxertos , Transplante de Fígado , Transplante Heterólogo , Animais , Animais Geneticamente Modificados , Células Endoteliais/metabolismo , Humanos , Transplante de Fígado/métodos , Suínos , Transplante Heterólogo/métodos
11.
Epigenomics ; 11(1): 53-63, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30444423

RESUMO

AIM: We aimed to identify the roles of circRHOT1 in pancreatic cancer. MATERIALS & METHODS: The circRHOT1 was acquired from our previous study followed by quantitative real-time PCR and fluorescence in situ hybridization validation in pancreatic cancer. We used siRNA and shRNA to explore the function of circRHOT1 in pancreatic cancer cells. Bioinformatic analyses were applied to study the potential mechanism of circRHOT1. RESULTS: The circRHOT1 was upregulated in pancreatic cancer and predominantly located in the cytoplasm. Reducing the circRHOT1 expression may inhibit the pancreatic cancer cell proliferation, invasion and migration. The circRHOT1 may play a role in pancreatic cancer through binding miR-26b, miR-125a, miR-330 and miR-382 to regulate multiple tumor-associated pathways. CONCLUSION: This study demonstrated that circRHOT1 may serve as an oncogenic circRNA that promotes tumor progression.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas Mitocondriais/genética , Neoplasias Pancreáticas/genética , RNA , Proteínas rho de Ligação ao GTP/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Hibridização in Situ Fluorescente , MicroRNAs/genética , Neoplasias Pancreáticas/patologia , Interferência de RNA , RNA Circular
12.
Oncogene ; 37(50): 6399-6413, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30068940

RESUMO

Nuclear-enriched RNA-binding proteins (RBPs) are mainly involved in transcriptional regulation, which is a critical checkpoint to tune gene diversity and expression levels. We analyzed nuclear RBPs in human HCC tissues and matched normal control tissues. Based on the gene expression levels, PTBP3 was identified as top-ranked in the nuclei of HCC cells. HCC cell lines then were transfected with siRNAs or lentiviral vectors. PTBP3 promoted HCC cell proliferation and metastasis both in vitro and in vivo. RNA immunoprecipitation (RIP), fluorescence in situ hybridization (FISH) and qRT-PCR assays verified that PTBP3 protein recruited abundant lnc-NEAT1 splicing variants (NEAT1_1 and NEAT1_2) and pre-miR-612 (precursor of miR-612) in the nucleus. NEAT1_1, NEAT1_2 and miR-612 expression levels were determined by PTBP3. Correlational analyses revealed that PTBP3 was positively correlated with NEAT1, but it was inversely correlated with miR-612 in HCC. The P53/CCND1 and AKT2/EMT pathways were determined by NEAT1 and miR-612 respectively in HCC. The PTBP3high and NEAT1high/miR-612low patients had a shorter overall survival. Therefore, nuclear-enriched RBP, PTBP3, promotes HCC cell malignant growth and metastasis by regulating the balance of splicing variants (NEAT1_1, NEAT1_2 and miR-612) in HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/patologia , MicroRNAs/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , RNA Longo não Codificante/genética , Animais , Carcinoma Hepatocelular/metabolismo , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo
13.
Cancer Lett ; 414: 301-309, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29174799

RESUMO

Circular RNAs (circRNAs) are a class of single-stranded closed RNA molecules that undergo a specific backsplicing from pre-mRNA. With the application of high-throughput sequencing and bioinformatics, circRNAs are found to be widely expressed across species. Some functionally characterized circRNAs have critical roles in gene regulation through various actions, including sponging microRNAs and proteins as well as regulating transcription and splicing. Moreover, most circRNAs are aberrantly expressed in different cancer types, and some of them have been reported to play important roles in the development and progression of cancer. Given the lack of a 5' cap structure and evidence of their ability to bind with ribosomes, circRNAs were generally considered as noncoding RNA. Notably, recent studies reported that endogenous circRNAs can be translated with a cap-independent manner, which redefines the functional roles of circRNA, further expanding the complexity of eukaryotic transcriptomes. This review aims to re-evaluate the functions and roles of circRNA from the cancer perspective. It discusses the current understanding of circRNA functions, the emerging roles of circRNA in cancer, and the challenges of future studies.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Biossíntese de Proteínas/genética , RNA/genética , Progressão da Doença , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Modelos Genéticos , Neoplasias/metabolismo , Neoplasias/patologia , Ligação Proteica , RNA/metabolismo , RNA Circular
14.
Cancer Med ; 6(8): 1941-1951, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28675698

RESUMO

Autophagy is a life phenomenon in which autophagosomes remove damaged or aging organelles and long-lived circulating proteins to maintain the cell's stability. However, disorders of excessive autophagy are a response of cancer cells to a variety of anticancer treatments which lead to cancer cell death. The Akt/mammalian target of rapamycin (mTOR) and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathways are both involved in nutrient-induced autophagic phenomenon and exhibit vital relevance to oncogenesis in various cancer cell types, including hepatocellular carcinoma (HCC). However, the influence of autophagy for cancer cell death remains controversial and few scientists have investigated the variation of these two signaling pathways in cancer cell autophagic phenomenon induced by anticancer treatment simultaneously. Here, we explored the anticancer efficacy and mechanisms of glycyrrhizin (GL), a bioactive compound of licorice with little toxicity in normal cells. It is interesting that inhibition of Akt/mTOR signaling in concurrence with enhanced ERK1/2 activity exists in GL-induced autophagy and cytotoxicity in HepG2 and MHCC97-H hepatocellular carcinoma cells. These results imply that the GL-related anticancer ability might correlate with the induction of autophagy. The influence of induced autophagic phenomenon on cell viability might depend on the severity of autophagy and be pathway specific. In the subsequent subcutaneous xenograft experiment in vivo with MHCC97-H cells, GL obviously exhibited its inhibitory efficacy in tumor growth via inducing excess autophagy in MHCC97-H cells (P < 0.05). Our data prompt that GL possesses a property of excess autophagic phenomenon induction in HCC and exerts high anticancer efficacy in vitro and in vivo. This warrants further investigation toward possible clinical applications in patients with HCC.


Assuntos
Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Ácido Glicirrízico/farmacologia , Neoplasias Hepáticas/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Ácido Glicirrízico/química , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
RNA Biol ; 14(8): 992-999, 2017 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-27617908

RESUMO

Circular RNAs (circRNAs) are a novel class of non-coding RNA that assumes a covalently closed continuous conformation. CircRNAs were previously thought to be the byproducts of splicing errors caused by low abundance and the technological limitations. With the recent development of high-throughput sequencing technology, numerous circRNAs have been discovered in many species. Recent studies have revealed that circRNAs are stable and widely expressed, and often exhibit cell type-specific or tissue-specific expression. Most circRNAs can be generated from exons, introns, or both. Remarkably, emerging evidence indicates that some circRNAs can serve as microRNA (miRNA) sponges, regulate transcription or splicing, and can interact with RNA binding proteins (RBPs). Moreover, circRNAs have been reported to play essential roles in myriad life processes, such as aging, insulin secretion, tissue development, atherosclerotic vascular disease risk, cardiac hypertrophy and cancer. Although circRNAs are ancient molecules, they represent a newly appreciated form of noncoding RNA and as such have great potential implications in clinical and research fields. Here, we review the current understanding of circRNA classification, function and significance in physiological and pathological processes. We believe that future research will increase our understanding of the regulation and function of these novel molecules.


Assuntos
Aterosclerose/genética , Cardiomegalia/genética , MicroRNAs/genética , Neoplasias/genética , Splicing de RNA , RNA/genética , Aterosclerose/diagnóstico , Aterosclerose/metabolismo , Aterosclerose/patologia , Pareamento de Bases , Biomarcadores/metabolismo , Cardiomegalia/diagnóstico , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Éxons , Humanos , Íntrons , MicroRNAs/metabolismo , Neoplasias/diagnóstico , Neoplasias/metabolismo , Neoplasias/patologia , RNA/classificação , RNA/metabolismo , RNA Circular
16.
World J Gastroenterol ; 22(45): 9933-9943, 2016 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-28018100

RESUMO

Hepatocellular carcinoma (HCC) is one of the most lethal cancers, and its rate of incidence is rising annually. Despite the progress in diagnosis and treatment, the overall prognoses of HCC patients remain dismal due to the difficulties in early diagnosis and the high level of tumor invasion, metastasis and recurrence. It is urgent to explore the underlying mechanism of HCC carcinogenesis and progression to find out the specific biomarkers for HCC early diagnosis and the promising target for HCC chemotherapy. Recently, the reprogramming of cancer metabolism has been identified as a hallmark of cancer. The shift from the oxidative phosphorylation metabolic pathway to the glycolysis pathway in HCC meets the demands of rapid cell proliferation and offers a favorable microenvironment for tumor progression. Such metabolic reprogramming could be considered as a critical link between the different HCC genotypes and phenotypes. The regulation of metabolic reprogramming in cancer is complex and may occur via genetic mutations and epigenetic modulations including oncogenes, tumor suppressor genes, signaling pathways, noncoding RNAs, and glycolytic enzymes etc. Understanding the regulatory mechanisms of glycolysis in HCC may enrich our knowledge of hepatocellular carcinogenesis and provide important foundations in the search for novel diagnostic biomarkers and promising therapeutic targets for HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Glucose/metabolismo , Glicólise/genética , Neoplasias Hepáticas/metabolismo , Fosforilação Oxidativa , Epigênese Genética , Genes Supressores de Tumor , Humanos , Mutação , Oncogenes , RNA não Traduzido , Transdução de Sinais
17.
Cell Physiol Biochem ; 40(6): 1334-1344, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27997903

RESUMO

BACKGROUND/AIMS: Circular RNAs (circRNAs) are a special novel type of a stable, diverse and conserved noncoding RNA in mammalian cells. Particularly in cancer, circRNAs have been reported to be widely involved in the physiological/pathological process of life. However, it is unclear whether circRNAs are specifically involved in pancreatic ductal adenocarcinoma (PDAC). METHODS: We investigated the expression profile of circRNAs in six PDAC cancer samples and paired adjacent normal tissues using microarray. A high-throughput circRNA microarray was used to identify dysregulated circular RNAs in six PDAC patients. Bioinformatic analyses were applied to study these differentially expressed circRNAs. Furthermore, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to confirm these results. RESULTS: We revealed and confirmed that a number of circRNAs were dysregulated, which suggests a potential role in pancreatic cancer. CONCLUSIONS: this study demonstrates that clusters of circRNAs are aberrantly expressed in PDAC compared with normal samples and provides new potential targets for the future treatment of PDAC and novel insights into PDAC biology.


Assuntos
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Neoplasias Pancreáticas/genética , RNA/genética , Adulto , Idoso , Sequência de Bases , Feminino , Ontologia Genética , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Anotação de Sequência Molecular , RNA/metabolismo , RNA Circular , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Transdução de Sinais/genética
18.
Oncotarget ; 7(10): 11595-608, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26871477

RESUMO

MicroRNA-150 (miR-150) is frequently dysregulated in cancer and is involved in carcinogenesis and cancer progression. In this study, we found that miR-150 was significantly downregulated in hepatocellular carcinoma (HCC) tissues compared to adjacent noncancerous tissues. Low levels of miR-150 were significantly associated with worse clinicopathological characteristics and a poor prognosis for patients with HCC. miR-150 overexpression inhibited cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo. Further experiments indicated that Grb2-associated binding protein 1 (GAB1) was a direct target of miR-150 in HCC cells. In addition, GAB1 expression was increased in HCC tissues and inversely correlated with miR-150 levels. Knockdown of GAB1 mimicked the tumor-suppressive effects of miR-150 overexpression on HCC cells, whereas restoration of GAB1 expression partially abolished the inhibitory effects. Moreover, miR-150 overexpression decreased GAB1 expression, subsequently downregulated phospho-ERK1/2 and suppressed epithelial-mesenchymal-transition (EMT). These effects caused by miR-150 overexpression were alleviated by exogenous GAB1 expression. Taken together, this study demonstrates that miR-150 may be useful as a prognostic marker and that the identified miR-150-GAB1-ERK axis is a potential therapeutic target for HCC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Carcinoma Hepatocelular/genética , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Neoplasias Hepáticas/genética , Sistema de Sinalização das MAP Quinases , MicroRNAs/genética , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Transição Epitelial-Mesenquimal , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/biossíntese , Pessoa de Meia-Idade , Metástase Neoplásica , Transfecção
19.
Tumour Biol ; 37(4): 5097-105, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26546438

RESUMO

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancer worldwide. However, the mechanism underlying the HCC development remains unclear. Ras-related associated with diabetes (RRAD) is a small Ras-related GTPase which has been implicated in metabolic disease and several types of cancer, yet its functions in HCC remain unknown. A tissue microarray constructed by 90 paired HCC tissues and adjacent non-cancerous liver tissues was used to examine the protein levels of RRAD, and the messenger RNA (mRNA) expression of RRAD was also detected in a subset of this cohort. The prognostic significance of RRAD was estimated by the Kaplan-Meier analysis and Cox regression. The glucose utilization assay and lactate production assay were performed to measure the role of RRAD in HCC glycolysis. The effect of RRAD in HCC invasion and metastasis was analyzed by transwell assays. Our results suggested that the expression of RRAD was downregulated in HCC tissues compared to the adjacent non-tumorous liver tissues both in mRNA and protein levels and lower RRAD expression served as an independent prognostic indicator for the survival of HCC patients. Moreover, RRAD inhibited hepatoma cell aerobic glycolysis by negatively regulating the expression of glucose transporter 1 (GLUT1) and hexokinase II (HK-II). In addition, RRAD inhibition dramatically increased hepatoma cell invasion and metastasis. In conclusion, our study revealed that RRAD expression was decreased in HCC tumor tissues and predicted poor clinical outcome for HCC patients and played an important role in regulating aerobic glycolysis and cell invasion and metastasis and may represent potential targets for improving the treatment of HCC.


Assuntos
Biomarcadores Tumorais/biossíntese , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteínas ras/biossíntese , Adulto , Aerobiose , Idoso , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Transportador de Glucose Tipo 1/biossíntese , Glicólise/genética , Células Hep G2 , Hexoquinase/biossíntese , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Prognóstico , Análise Serial de Tecidos , Proteínas ras/genética
20.
Tumour Biol ; 37(3): 3933-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26482611

RESUMO

Long noncoding RNAs (lncRNAs) have been shown to play critical roles in the development and progression of diseases. lncRNA activated by transforming growth factor beta (TGF-ß) (lncRNA-ATB) was discovered as a prognostic factor in hepatocellular carcinoma, gastric cancer, and colorectal cancer. However, little is known about the role of lncRNA-ATB in pancreatic cancer. This study aimed to assess lncRNA-ATB expression in pancreatic cancer and explore its role in pancreatic cancer pathogenesis. Quantitative real-time polymerase chain reaction was performed to detect lncRNA-ATB expression in 150 pancreatic cancer tissues and five pancreatic cancer cell lines compared to paired adjacent normal tissues and normal human pancreatic ductal epithelial cell line HPDE6c-7. The correlations between lncRNA-ATB expression and clinicopathological characteristics and prognosis were also analyzed. We found that lncRNA-ATB expression was decreased in pancreatic cancer tissues and pancreatic cancer cell lines. Low lncRNA-ATB expression levels were significantly correlated with lymph node metastases (yes vs. no, P = 0.009), neural invasion (positive vs. negative, P = 0.049), and clinical stage (early stage vs. advanced stage, P = 0.014). Moreover, patients with low lncRNA-ATB expression levels exhibited markedly worse overall survival prognoses (P < 0.001). Multivariate analysis indicated that decreased lncRNA-ATB expression was an independent predictor of poor prognosis in pancreatic cancer patients (P = 0.005). In conclusion, lncRNA-ATB may play a critical role in pancreatic cancer progression and prognosis and may serve as a potential prognostic biomarker in pancreatic cancer patients.


Assuntos
Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , RNA Longo não Codificante/genética , Fator de Crescimento Transformador beta/genética , Linhagem Celular , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase Via Transcriptase Reversa/estatística & dados numéricos
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